Luzum, J A; Pakyz, R E; Elsey, A R; Haidar, C E; Peterson, J F; Whirl-Carrillo, M; Handelman, S K; Palmer, K; Pulley, J M; Beller, M; Schildcrout, J S; Field, J R; Weitzel, K W; Cooper-DeHoff, R M; Cavallari, L H; O'Donnell, P H; Altman, R B; Pereira, N; Ratain, M J; Roden, D M; Embi, P J; Sadee, W; Klein, T E; Johnson, J A; Relling, M V; Wang, L; Weinshilboum, R M; Shuldiner, A R; Freimuth, R R
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. © 2017, The American Society for Clinical Pharmacology and Therapeutics.
Shuldiner, AR; Relling, MV; Peterson, JF; Hicks, JK; Freimuth, RR; Sadee, W; Pereira, NL; Roden, DM; Johnson, JA; Klein, TE
The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real-world solutions to implementation of evidence-based pharmacogenetic tests in diverse health-care settings. Dissemination of the resulting toolbox of “implementation best practices” will prove useful to a broad audience. PMID:23588301
Giacomini, KM; Brett, CM; Altman, RB; Benowitz, NL; Dolan, ME; Flockhart, DA; Johnson, JA; Hayes, DF; Klein, T; Krauss, RM; Kroetz, DL; McLeod, HL; Nguyen, AT; Ratain, MJ; Relling, MV; Reus, V; Roden, DM; Schaefer, CA; Shuldiner, AR; Skaar, T; Tantisira, K; Tyndale, RF; Wang, L; Weinshilboum, RM; Weiss, ST; Zineh, I
The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism. PMID:17339863
Srinivasan, Balaji S; Chen, Jinbo; Cheng, Cheng; Conti, David; Duan, Shiwei; Fridley, Brooke L; Gu, Xiangjun; Haines, Jonathan L; Jorgenson, Eric; Kraja, Aldi; Lasky–Su, Jessica; Li, Lang; Rodin, Andrei; Wang, Dai; Province, Mike; Ritchie, Marylyn D
Each year, the Pharmacogenetics Research Network (PGRN) holds an analysis workshop for the members of the PGRN to share new methodologies, study design approaches and to discuss real data applications. This event is closed to members of the PGRN, but the methods presented are relevant to others conducting pharmacogenomics research. This special report describes many of the novel approaches discussed at the workshop and provides a resource for investigators in the field performing pharmacogenomics data analysis. While the focus is pharmacogenomics, the methods discussed are far ranging and have relevance to all types of genetic association studies: identifying noncoding variants and tag-SNPs, haplotype analysis, multivariate techniques, quantitative trait analysis, gene–gene and gene–environment interactions, and genome-wide association studies. The goal is to introduce readers to the topics discussed at the workshop and provide a direction for future development of analysis tools and methods for analysis of pharmacogenomic data. PMID:19207025
Srinivasan, Balaji S; Chen, Jinbo; Cheng, Cheng; Conti, David; Duan, Shiwei; Fridley, Brooke L; Gu, Xiangjun; Haines, Jonathan L; Jorgenson, Eric; Kraja, Aldi; Lasky-Su, Jessica; Li, Lang; Rodin, Andrei; Wang, Dai; Province, Mike; Ritchie, Marylyn D
Each year, the Pharmacogenetics Research Network (PGRN) holds an analysis workshop for the members of the PGRN to share new methodologies, study design approaches and to discuss real data applications. This event is closed to members of the PGRN, but the methods presented are relevant to others conducting pharmacogenomics research. This special report describes many of the novel approaches discussed at the workshop and provides a resource for investigators in the field performing pharmacogenomics data analysis. While the focus is pharmacogenomics, the methods discussed are far ranging and have relevance to all types of genetic association studies: identifying noncoding variants and tag-SNPs, haplotype analysis, multivariate techniques, quantitative trait analysis, gene-gene and gene-environment interactions, and genome-wide association studies. The goal is to introduce readers to the topics discussed at the workshop and provide a direction for future development of analysis tools and methods for analysis of pharmacogenomic data.
Daud, Aizati N A; Bergsma, Eefke L; Bergman, Jorieke E H; De Walle, Hermien E K; Kerstjens-Frederikse, Wilhelmina S; Bijker, Bert J; Hak, Eelko; Wilffert, Bob
Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome.
Bailey, Kent R; Cheng, Cheng
Will genome-wide association studies (GWAS) 'work' for pharmacogenetics research? This question was the topic of a staged debate, with pro and con sides, aimed to bring out the strengths and weaknesses of GWAS for pharmacogenetics studies. After a full day of seminars at the Fifth Statistical Analysis Workshop of the Pharmacogenetics Research Network, the lively debate was held--appropriately--at Goonies Comedy Club in Rochester (MN, USA). The pro side emphasized that the many GWAS successes for identifying genetic variants associated with disease risk show that it works; that the current genotyping platforms are efficient, with good imputation methods to fill in missing data; that its global assessment is always a success even if no significant associations are detected; and that genetic effects are likely to be large because humans have not evolved in a drug-therapy environment. By contrast, the con side emphasized that we have limited knowledge of the complexity of the genome; limited clinical phenotypes compromise studies; the likely multifactorial nature of drug response clouding the small genetic effects; and limitations of sample size and replication studies in pharmacogenetic studies. Lively and insightful discussions emphasized further research efforts that might benefit GWAS in pharmacogenetics.
Quaranta, Sylvie; Dupouey, Julien; Colle, Romain; Verstuyft, Céline
Tailoring antidepressant drug therapy to each individual patient is a complex process because these drugs have adverse effects leading to discontinuation. Pharmacogenetics may provide useful information in routine practice for optimizing antidepressant treatment by helping limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for P450 cytochromes CYP2C19 and CYP2D6 in psychiatric patients taking antidepressants. Depending on the level of evidence, the French National Network of Pharmacogenetics (RNPGx) has issued recommendations stating that pharmacogenetic tests for CYP2D6 and CYP2C19 genes are potentially useful in psychiatric patients treated with antidepressant drugs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Picard, Nicolas; Boyer, Jean-Christophe; Etienne-Grimaldi, Marie-Christine; Barin-Le Guellec, Chantal; Thomas, Fabienne; Loriot, Marie-Anne
More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the data provided (if any) are generally insufficient to ascertain whether a test is required and if it is useful. This article discusses the rationale for evaluating the performance and clinical usefulness of pharmacogenetics and provides, on behalf of the French national network of pharmacogenetics (RNPGx), three levels of recommendation for testing: essential, advisable, and possibly helpful. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Prakash, Swayam; Agrawal, Suraksha
Human genome sequencing highlights the involvement of genetic variation towards differential risk of human diseases, presence of different phenotypes, and response to pharmacological elements. This brings the field of personalized medicine to forefront in the era of modern health care. Numerous recent approaches have shown that how variation in the genome at single nucleotide level can be used in pharmacological research. The two broad aspects that deal with pharmacological research are pharmacogenetics and pharmacogenomics. This review encompasses how these variations have created the basis of pharmacogenetics and pharmacogenomics research and important milestones accomplished in these two fields in different diseases. It further discusses at length their importance in disease diagnosis, response of drugs, and various treatment modalities on the basis of genetic determinants.
Falcone, Mary; Smith, Ryan M; Chenoweth, Meghan J; Kumar Bhattacharjee, Abesh; Kelsoe, John R; Tyndale, Rachel F; Lerman, Caryn
The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment. PMID:23793356
Céspedes-Garro, Carolina; Naranjo, María-Eugenia G; Rodrigues-Soares, Fernanda; LLerena, Adrián; Duconge, Jorge; Montané-Jaime, Lazara K; Roblejo, Hilda; Fariñas, Humberto; Campos, María de Los A; Ramírez, Ronald; Serrano, Víctor; Villagrán, Carmen I; Peñas-LLedó, Eva M
The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including 'phenotyping probe drugs' for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients). The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine.
Céspedes-Garro, Carolina; Naranjo, María-Eugenia G; Rodrigues-Soares, Fernanda; LLerena, Adrián; Duconge, Jorge; Montané-Jaime, Lazara K; Roblejo, Hilda; Fariñas, Humberto; Campos, María de los A; Ramírez, Ronald; Serrano, Víctor; Villagrán, Carmen I; Peñas-LLedó, Eva M
Aim: The present review was aimed at analyzing the pharmacogenetic scientific activity in Central America and the Caribbean. Materials & methods: A literature search for pharmacogenetic studies in each country of the region was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers including ‘phenotyping probe drugs’ for major drug metabolizing enzymes. The review included 132 papers involving 47 biomarkers and 35,079 subjects (11,129 healthy volunteers and 23,950 patients). Results: The country with the most intensive pharmacogenetic research was Costa Rica. The most studied medical therapeutic area was oncology, and the most investigated biomarkers were CYP2D6 and HLA-A/B. Conclusion: Research activity on pharmacogenetics in Central American and the Caribbean populations is limited or absent. Therefore, strategies to promote effective collaborations, and foster interregional initiatives and research efforts among countries from the region could help for the rational clinical implementation of pharmacogenetics and personalized medicine. PMID:27633613
Quaranta, Sylvie; Thomas, Fabienne
Individualized treatment is of special importance in oncology because the drugs used for chemotherapy have a very narrow therapeutic index. Pharmacogenetics may contribute substantially to clinical routine for optimizing cancer treatment to limit toxic effects while maintaining efficacy. This review presents the usefulness of pharmacogenetic tests for some key applications: dihydropyrimidine dehydrogenase (DPYD) genotyping for fluoropyrimidine (5-fluorouracil, capecitabine), UDP glucuronosylstransferase (UGT1A1) for irinotecan and thiopurine S-methyltransferase (TPMT) for thiopurine drugs. Depending on the level of evidence, the French National Network of Pharmacogenetics (RNPGx) has issued three levels of recommendations for these pharmacogenetic tests: essential, advisable, and potentially useful. Other applications, for which the level of evidence is still discussed, will be evoked in the final section of this review. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Cohen, Mindy; Sadhasivam, Senthilkumar; Vinks, Alexander A
This review will discuss the most recent developments in pharmacogenetics of commonly used perioperative medications, new collaboration networks in the field of personalized medicine, and future clinical implications of pharmacogenetics. Evidence now suggests that pharmacogenetics has a role in the effects of analgesic, sedative, beta-blocker, local anesthetic, antiemetic, and obstetric medications. Variants in the μ opioid receptor gene change the analgesic effects of morphine. Additional opioids recently studied include remifentanil, methadone, tramadol, and codeine. Ibuprofen's clearance varies with CYP2C9*3 genotype. Midazolam is primarily metabolized by the CYP3A4/CYP3A5 enzymes. Enzyme induction was found to be about 50% greater with CYP3A5*3 homozygous genotype. Variations in minimum alveolar concentrations of volatile anesthetics and subcutaneous lidocaine efficacy have been attributed in part to melanocortin-1 receptor variants. Metoprolol achieved different effects in patients with CYP2D6 and beta1-receptor polymorphisms. Genetic background of the beta2-receptor contributes to susceptibility for experiencing preterm labor. The Pharmacogenomics Research Network and the Clinical Pharmacogenetics Implementation Consortium are partnerships of researchers who are dedicated to elucidating how the genome contributes to an individual patient's medication responses. In the near future, pharmacogenetic approaches may facilitate personalized perioperative intervention trials.
Morales, Chelsea T.; Muzquiz, LeeAnna I.; Howlett, Kevin; Azure, Bernie; Bodnar, Brenda; Finley, Vernon; Incashola, Tony; Mathias, Cheryl; Laukes, Cindi; Beatty, Patrick; Burke, Wylie; Pershouse, Mark A.; Putnam, Elizabeth A.; Trinidad, Susan Brown; James, Rosalina; Woodahl, Erica L.
Background Inclusion of American Indian and Alaska Native (AI/AN) populations in pharmacogenetic research is key if the benefits of pharmacogenetic testing are to reach these communities. Community-based participatory research (CBPR) offers a model to engage these communities in pharmacogenetics. Objectives An academic-community partnership between the University of Montana and the Confederated Salish and Kootenai Tribes (CSKT) was established to engage the community as partners and advisors in pharmacogenetic research. Methods A community advisory committee, the Community Pharmacogenetics Advisory Council (CPAC), was established to ensure community involvement in the research process. To promote bidirectional learning, researchers gave workshops and presentations about pharmacogenetic research to increase research capacity and CPAC members trained researchers in cultural competencies. As part of our commitment to a sustainable relationship, we conducted a self-assessment of the partnership, which included surveys and interviews with CPAC members and researchers. Results Academic and community participants agree that the partnership has promoted a bidirectional exchange of knowledge. Interviews showed positive feedback from the perspectives of both the CPAC and researchers. CPAC members discussed their trust in and support of the partnership as well as having learned more about research processes and pharmacogenetics. Researchers discussed their appreciation of CPAC involvement in the project and guidance the group provided in understanding the CSKT community and culture. Discussion We have created an academic-community partnership to ensure CSKT community input and to share decision-making about pharmacogenetic research. Our CBPR approach may be a model for engaging AI/AN people, and other underserved populations, in genetic research. PMID:27346763
Grayson, David S; Bliss-Moreau, Eliza; Machado, Christopher J; Bennett, Jeffrey; Shen, Kelly; Grant, Kathleen A; Fair, Damien A; Amaral1, David G
Summary Contemporary research suggests that the mammalian brain is a complex system, implying that damage to even a single functional area could have widespread consequences across the system. To test this hypothesis, we pharmacogenetically inactivated the rhesus monkey amygdala, a subcortical region with distributed and well-defined cortical connectivity. We then examined the impact of that perturbation on global network organization using resting-state functional connectivity MRI. Amygdala inactivation disrupted amygdalocortical communication and distributed corticocortical coupling across multiple functional brain systems. Altered coupling was explained using a graph-based analysis of experimentally established structural connectivity to simulate disconnection of the amygdala. Communication capacity via monosynaptic and polysynaptic pathways, in aggregate, largely accounted for the correlational structure of endogenous brain activity and many of the non-local changes that resulted from amygdala inactivation. These results highlight the structural basis of distributed neural activity and suggest a strategy for linking focal neuropathology to remote neurophysiological changes. PMID:27477019
García-González, Xandra; Cabaleiro, Teresa; Herrero, María José; McLeod, Howard; López-Fernández, Luis A
In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain. It is based on lectures presented by speakers of the Clinical Implementation of Pharmacogenetics Symposium at the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held in April 20, 2015.
Robinson, Renee; Starks, Helene; Burke, Wylie; Dillard, Denise A.
Objectives. Pharmacogenetic research and clinical testing raise important concerns for individuals and communities, especially where past medical research and practice has perpetrated harm and cultivated distrust of health care systems and clinicians. We investigated perceptions of pharmacogenetics among Alaska Native (AN) people. Methods. We held four focus groups for 32 ANs in south central Alaska to elicit views about pharmacogenetics in general and for treatment of cardiovascular disease, breast cancer, depression, and nicotine addiction. We analyzed data for perceived risks and rewards of pharmacogenetics. Results. Potential risks of pharmacogenetics included health care rationing, misuse of information, and stigma to individuals and the AN community. Potential rewards included decreased care costs, improved outcomes, and community development. Participants also discussed 8 contingent conditions that could mitigate risks and increase pharmacogenetic acceptability. Conclusions. Alaska Natives perceive pharmacogenetics as potentially benefitting and harming individuals, communities, and health systems, depending on methods and oversight. Researchers, clinicians, and administrators, especially in community-based clinic and health care systems serving minority populations, must address this “double-edged sword” to effectively conduct pharmacogenetics. PMID:24134351
Malhotra, A K; Zhang, J-P; Lencz, T
Pharmacogenetic/pharmacogenomic (PGx) approaches to psychopharmacology aim to identify clinically meaningful predictors of drug efficacy and/or side-effect burden. To date, however, PGx studies in psychiatry have not yielded compelling results, and clinical utilization of PGx testing in psychiatry is extremely limited. In this review, the authors provide a brief overview on the status of PGx studies in psychiatry, review the commercialization process for PGx tests and then discuss methodological considerations that may enhance the potential for clinically applicable PGx tests in psychiatry. The authors focus on design considerations that include increased ascertainment of subjects in the earliest phases of illness, discuss the advantages of drug-induced adverse events as phenotypes for examination and emphasize the importance of maximizing adherence to treatment in pharmacogenetic studies. Finally, the authors discuss unique aspects of pharmacogenetic studies that may distinguish them from studies of other complex traits. Taken together, these data provide insights into the design and methodological considerations that may enhance the potential for clinical utility of PGx studies.
Avey, Jaedon P; Hiratsuka, Vanessa Y; Beans, Julie A; Trinidad, Susan Brown; Tyndale, Rachel F; Robinson, Renee F
Aim: Describe patients,’ providers’ and healthcare system leaders’ perceptions of pharmacogenetic research to guide tobacco cessation treatment in an American Indian/Alaska Native primary care setting. Materials & methods: This qualitative study used semistructured interviews with 20 American Indian/Alaska Native current or former tobacco users, 12 healthcare providers and nine healthcare system leaders. Results: Participants supported pharmacogenetic research to guide tobacco cessation treatment provided that a community-based participatory research approach be employed, research closely coordinate with existing tobacco cessation services and access to pharmacogenetic test results be restricted to providers involved in tobacco cessation. Conclusion: Despite a history of mistrust toward genetic research in tribal communities, participants expressed willingness to support pharmacogenetic research to guide tobacco cessation treatment. PMID:26871371
Lin, Chao-Cheng; Wang, Ying-Chieh; Chen, Jen-Yeu; Liou, Ying-Jay; Bai, Ya-Mei; Lai, I-Ching; Chen, Tzu-Ting; Chiu, Hung-Wen; Li, Yu-Chuan
Although one third to one half of refractory schizophrenic patients responds to clozapine, however, there are few evidences currently that could predict clozapine response before the use of the medication. The present study aimed to train and validate artificial neural networks (ANN), using clinical and pharmacogenetic data, to predict clozapine response in schizophrenic patients. Five pharmacogenetic variables and five clinical variables were collated from 93 schizophrenic patients taking clozapine, including 26 responders. ANN analysis was carried out by training the network with data from 75% of cases and subsequently testing with data from 25% of unseen cases to determine the optimal ANN architecture. Then the leave-one-out method was used to examine the generalization of the models. The optimal ANN architecture was found to be a standard feed-forward, fully-connected, back-propagation multilayer perceptron. The overall accuracy rate of ANN was 83.3%, which is higher than that of logistic regression (LR) (70.8%). By using the area under the receiver operating characteristics curve as a measure of performance, the ANN outperformed the LR (0.821+/-0.054 versus 0.579+/-0.068; p<0.001). The ANN with only genetic variables outperformed the ANN with only clinical variables (0.805+/-0.056 versus 0.647+/-0.066; p=0.046). The gene polymorphisms should play an important role in the prediction. Further validation of ANN analysis is likely to provide decision support for predicting individual response.
Lamoureux, Fabien; Duflot, Thomas
The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Crosslin, David R; Robertson, Peggy D; Carrell, David S; Gordon, Adam S; Hanna, David S; Burt, Amber; Fullerton, Stephanie M; Scrol, Aaron; Ralston, James; Leppig, Kathleen; Hartzler, Andrea; Baldwin, Eric; Andrade, Mariza de; Kullo, Iftikhar J; Tromp, Gerard; Doheny, Kimberly F; Ritchie, Marylyn D; Crane, Paul K; Nickerson, Deborah A; Larson, Eric B; Jarvik, Gail P
In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations. To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples. We then selected 450 of those to be re-consented, to redraw blood, and ultimately to validate CLIA variants in anticipation of returning the results to the participant and EHR. These 450 were selected using an algorithm we designed to harness data from self-reported race, diagnosis and procedure codes, medical notes, laboratory results, and variant-level bioinformatics to ensure selection of an informative sample. We annotated the multi-sample variant call format by a combination of SeattleSeq and SnpEff tools, with additional custom variables including evidence from ClinVar, OMIM, HGMD, and prior clinical associations. We focused our analyses on 27 actionable genes, largely driven by the Clinical Pharmacogenetics Implementation Consortium. We derived a ranking system based on the total number of coding variants per participant (75.2±14.7), and the number of coding variants with high or moderate impact (11.5±3.9). Notably, we identified 11 stop-gained (1 %) and 519 missense (20 %) variants out of a total of 1785 in these 27 genes. Finally, we prioritized variants to be returned to the EHR with prior clinical evidence of pathogenicity or annotated as stop-gain for the following genes: CACNA1S and RYR1 (malignant hyperthermia); SCN5A, KCNH2, and RYR2 (arrhythmia); and LDLR (high cholesterol). The incorporation of
Mackenzie, Peter I; Somogyi, Andrew A; Miners, John O
Metabolism facilitates the elimination, detoxification and excretion in urine or bile (as biotransformation products) of a myriad of structurally diverse drugs and other chemicals. The metabolism of drugs, non-drug xenobiotics and many endogenous compounds is catalyzed by families of drug metabolizing enzymes (DMEs). These include the hemoprotein-containing cytochromes P450, which function predominantly as monooxygenases, and conjugation enzymes that transfer a sugar, sulfate, acetate or glutathione moiety to substrates containing a suitable acceptor functional group. Drug and chemical metabolism, especially the enzymes that catalyse these reactions, has been the research focus of several groups in Australia for over four decades. In this review, we highlight the role of recent and current drug metabolism research in Australia, including elucidation of the structure and function of enzymes from the various DME families, factors that modulate enzyme activity in humans (e.g. drug-drug interactions, gene expression and genetic polymorphism) and the application of in vitro approaches for the prediction of drug metabolism parameters in humans, along with the broader pharmacological/clinical pharmacological and toxicological significance of drug metabolism and DMEs and their relevance to drug discovery and development, and to clinical practice.
Haga, Susanne B; Mills, Rachel; Moaddeb, Jivan
Advances in pharmacogenetic research have improved our understanding of adverse drug responses and have led to the development of pharmacogenetic tests and targeted drugs. However, the extent of the communication process and provision of information to patients about pharmacogenetics is unclear. Pharmacogenetic information may be included in sections of a drug’s package insert intended for patients, which is provided directly to patients or communicated via the health provider. To determine what pharmacogenetic information, if any, is included in patient-targeted sections of the drug label, we reviewed the labels listed in the US Food and Drug Administration’s Table of Pharmacogenomic Biomarkers in Drug Labels. To date, 140 drugs include pharmacogenetic-related information in the approved label. Our analysis revealed that pharmacogenetic information is included in patient-targeted sections for a minority (n=29; 21%) of drug labels, with no obvious pattern associated with the inclusion of pharmacogenetic information. Therefore, patients are unlikely to learn about pharmacogenetics through written materials dispensed with the drug. Given that there are also inconsistencies with regard to inclusion of pharmacogenetic information in the patient counseling information section, it is also unlikely that patients are receiving adequate pharmacogenetic information from their provider. The inconsistent presence of pharmacogenetic information in patient-targeted sections of drug labels suggests a need to review the criteria for inclusion of information in patient-targeted sections in order to increase consistency and patient knowledge of pharmacogenetic information. PMID:25342916
Stingl, J C; Brockmöller, J
The broad clinical application of pharmacogenetic diagnostics for individualised drug treatment is still limited. With the exception of oncological therapies where molecular tumor makers are frequently used to decide upon individual drug therapies, pharmacogenetic testing is not generally offered in clinical laboratory diagnostics, because the costs are not covered by general health insurance and it is not evident what consequences the results of a genotyping test may have for the individual drug treatment. Especially in the context of pharmacokinetics, bioequivalence-based concepts have been developed that allow the individual drug dosage or therapy to be adjusted to genetic polymorphisms in drug metabolism, drug transport that affect drug absorption, metabolism and elimination. Pharmacogenetic aspects are increasingly included in the product information (e.g., on its website the FDA lists more than 60 drug labels that include pharmacogenetic information). However, most pharmacogenetic information on drug labels does not give recommendations for clinical decisions to be made based on individual genotypes. This gap is currently being closed by the development of international consortia aiming to base clinical recommendations on the best available evidence by systematic review of the existing data. The Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC) is an international community-driven organisation that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). The aim of these guidelines is to give therapeutic recommendations such as dose adjustments or suggestions for the choice of an alternative drug in the case of specific genotypes (phenotypes) that predict slow metabolism or transport of drugs or safety risks or risks of therapeutic failure. These guidelines are not mandatory but serve to facilitate the translation of pharmacogenetic
Voora, Deepak; Ginsburg, Geoffrey S
Pharmacogenetics primarily uses genetic variation to identify subgroups of patients who may respond differently to a certain medication. Since its first description, the field of pharmacogenetics has expanded to study a broad range of cardiovascular drugs and has become a mainstream research discipline. Three principle classes of pharmacogenetic markers have emerged: 1) pharmacokinetic; 2) pharmacodynamic; and 3) underlying disease mechanism. In the realm of cardiovascular pharmacogenetics, significant advances have identified markers in each class for a variety of therapeutics, some with a potential for improving patient outcomes. While ongoing clinical trials will determine if routine use of pharmacogenetic testing may be beneficial, the data today support pharmacogenetic testing for certain variants on an individualized, case-by-case basis. Our primary goal is to review the association data for the major pharmacogenetic variants associated with commonly used cardiovascular medications: antiplatelet agents, warfarin, statins, beta-blockers, diuretics, and antiarrhythmic drugs. In addition, we highlight which variants and in which contexts pharmacogenetic testing can be implemented by practicing clinicians. The pace of genetic discovery has outstripped the generation of the evidence justifying its clinical adoption. Until the evidentiary gaps are filled, however, clinicians may choose to target therapeutics to individual patients whose genetic background indicates that they stand to benefit the most from pharmacogenetic testing.
Fricke-Galindo, Ingrid; Jung-Cook, Helgi; LLerena, Adrián; López-López, Marisol
Mexico presents a complex population diversity integrated by Mexican indigenous (MI) (7% of Mexico's population) and Mexican mestizos (MMs). This composition highlights the importance of pharmacogenetic studies in Mexican populations. The aims of this study were to analyze the reported frequencies of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in healthy volunteers from Mexican populations and to assess its interethnic variability across MI and MM populations. After a literature search in PubMed, and according to previously defined inclusion criteria, 63 pharmacogenetic studies performed in Mexican healthy volunteers up to date were selected. These reports comprised 56,292 healthy volunteers (71.58% MM). Allele frequencies in 31 pharmacogenetic biomarkers, from 121 searched, are described. Nine of these biomarkers presented variation within MM and MI groups. The frequencies of CYP2D6*3, *4, *5, *10, *17, *35 and *41 alleles in the MM group were different from those reported in the MI group. CYP2C9*2 and *3 alleles were more frequent in MM than in MI populations (χ2 test, p<0.05). CYP2C19*3 allele was not found in the MM or MI populations reported. For UGT1A1*28, only one study was found. HLA-A*31:01 and HLA-B*15:02 were present in some MM and MI populations. Poor metabolizers for CYP2D6 and CYP2C9 were more frequent in MM than in MI groups (χ2 test, p<0.05). Only 26% of the relevant pharmacogenetic biomarkers searched have been studied in Mexican healthy volunteers; therefore, further studies are warranted. The frequency variation of biomarkers in MM and MI populations could be important for the clinical implementation of pharmacogenetics in Mexico.
McIlleron, Helen; Abdel-Rahman, Susan; Dave, Joel Alex; Blockman, Marc; Owen, Andrew
Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug–drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials. PMID:26009615
Ueda, Mikito; Ishiguro, Shin; Watanabe, Takashi; Saeki, Yoshinori; Shimoda, Kazutaka
Pharmacogenetics/pharmacogenomics has been developed so rapidly in these twenty years and the pharmacogenetic/pharmacogenomic research in psychiatry is also the case. Especially, the impact of genetic polymorphism (e.g., cytochrome P450 (CYP)) on pharmacokinetics of psychotropics have been extensively studied, however, recently, most of the studies in this field have been moved to pharmacodynamic study, i.e., the studies on impact of genetics polymorphism on clinical response and adverse effects to pharmacotherapy with psychotropics. Development of pharmacogenetics/ pharmacogenomics in psychiatry may well lead to a future of individualized pharmacotherapy for psychiatric disorders.
Woillard, Jean-Baptiste; Chouchana, Laurent; Picard, Nicolas; Loriot, Marie-Anne
Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
Rodeiro, Idania; Remírez-Figueredo, Diadelis; García-Mesa, Milagros; Dorado, Pedro; LLerena, Adrián
Meeting report of the "Second Symposium on Pharmacology of Cytochrome P450 and Transporters" organized by the Cuban Society of Pharmacology in collaboration with the European Society of Pharmacogenetics and Theranostics (ESPT) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (www.ribef.com). The Symposium covered different topics on pharmacogenetics and its clinical implications, focusing on Latin-American populations. The activities of the ESPT were also presented and discussed. The topics addressed were regulatory aspects, the use of pharmacogenetics in pre-clinical research, herbal medicine, and natural products, ending with a discussion about translation into clinical practice, specifically for cardiovascular disorders and psychiatry. Finally, the implication for population diversity in Latin America was also discussed. The RIBEF initiative represents a promising step towards the inclusion of Latin American populations among those to benefit from the implementation of pharmacogenetics in clinical practice. Among current RIBEF activities, the CEIBA.FP Consortium aims to study the variability of pheno- and genotypes in Hispanics that are relevant to pharmacogenetics. For this purpose, populations from Mexico, Cuba, Nicaragua, Costa Rica, Ecuador, Colombia, Brasil, Perú, Chile, Uruguay, Argentina, Portugal, and Spain are currently being studied. The meeting's main conclusion was that population pharmacogenetic studies as well as academic clinical trials might need to be conducted in the different geographic locations/countries. This is important in order to improve drug safety, dosage recommendations, and pharmacovigilance programs, because environmental and ethnic factors vary across locations.
de Chaisemartin, L; Loriot, M-A
Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However, the narrow therapeutic index of most chemotherapeutic agents and the severe consequences of undertreatment or overdosing have led to research molecular predictive factors of the toxicity and efficacy of cancer treatments. Genetic factors affecting drug metabolism and transport partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of the treatments, that combines the optimal efficacy and the minimal risk of severe side effects. Polymorphisms in genes encoding specific drug-metabolising enzymes can result in individuals in the general population being characterised as low, rapid or even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available that determine or predict the metabolic status of an individual and, thus, enable the evaluation of risk of drug failure or toxicity. Some clinical applications of pharmacogenetics (5-FU, irinotecan, thiopurines) have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips...) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation, as a result of large international research projects (Human Genome Project, the 1000 Genomes Project International HapMap Project, and Programs for Genomic Applications NHLBI-PGA). This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer. For clinical use in the treatment of patients with colorectal cancer (CRC), in addition to fluoropyrimidines, another two new cytostatic drugs were allowed: irinotecan and oxaliplatin. Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted. The last 20 years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance. One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells. Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine. Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics. Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential. This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy. The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review. PMID:25110414
McIlleron, Helen; Abdel-Rahman, Susan; Dave, Joel Alex; Blockman, Marc; Owen, Andrew
Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug-drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: email@example.com.
Caudle, Kelly E.; Dunnenberger, Henry M.; Freimuth, Robert R.; Peterson, Josh F.; Burlison, Jonathan D.; Whirl-Carrillo, Michelle; Scott, Stuart A.; Rehm, Heidi L.; Williams, Marc S.; Klein, Teri E.; Relling, Mary V.; Hoffman, James M.
Introduction: Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes. Materials and methods: Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts. Results: Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms. Discussion: The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support. Genet Med 19 2, 215–223. PMID:27441996
Soofi, Hojjat; van Leeuwen, Evert
The one-size-fits-all paradigm of drug development fails to address inter-individual variability in drug response. Pharmacogenetics research aims at studying the role of genotypic differences in drug response. Recently, the pharmaceutical industry has shown interest to embed pharmacogenetics studies in the process of drug development. Nevertheless, population-based and commercial aspects of such future-oriented studies pose challenges for individually based informed consent (IC). As an exemplar of the communal turn to IC procedures, community advisory boards (CABs) have been integrated into different types of medical research. CABs hold the promise of organizing the relationship between participants and researchers in a more reciprocal and participatory way, offering possible means of overcoming the lapses of individualistic IC. However, the involvement of CABs with pharmacogenetics research might be rife with difficulties, uncertainties, and challenges. The current study first reviews the existing literature to discuss added values and challenges of relying on CABs as a supplement to individually based IC. Then, the particular moral and regulatory landscape of pharmacogenetics research will be delineated to argue that community engagement is both necessary and promising beyond the communal turn to IC processes. Three main features of the landscape include (1) new supportive stances that some regulatory bodies have adopted toward pharmacogenetics research, (2) the motivation of the industry to draw reception and trust from the subpopulations, and (3) the important role of the society in generating and embedding pharmacogenetics knowledge. Finally, some points to consider will be discussed to contextualize relying on CABs within this landscape.
Blakey, John D; Hall, Ian P
The study of genetic variation has the potential to aid understanding of the mechanisms underlying the observed inter-individual variation in drug response and by which idiosyncratic adverse effects occur. In this review, we outline current progress in pharmacogenetics using examples to highlight both mechanisms of influence of polymorphisms and research strategies for their detection. In the final sections we discuss contemporary challenges for both researchers and clinicians. PMID:21235621
Mestroni, Luisa; Begay, Rene; Graw, Sharon L; Taylor, Matthew RG
Purpose of Review Novel medical approaches and personalized medicine seek to use genetic information to “individualize” and improve diagnosis, prevention, and therapy. The personalized management of cardiovascular disease involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenetics in which individual genetic information is used to optimize pharmacological treatments. Recent Findings Evidence suggests that common polymorphic variants of modifier genes could influence drug response in cardiovascular disease in a variety of areas including heart failure, arrhythmias, dyslipidemia and hypertension. In heart failure, common genetic variants of beta-adrenergic receptors, alpha-adrenergic receptors, and endothelin receptors (among others) have been associated with variable response to heart failure therapies. The challenge remains to develop strategies to leverage this information in ways that personalize and optimize cardiovascular therapy based on a patient's genetic profile. Summary While advances in technologies will continue to transition personalized medicine from the research to the clinical setting, health care providers will need to reshape clinical diagnostic paradigms. Ultimately, pharmacogenetics will give providers options for improving patient management on the basis of pharmacogenetic data. PMID:24717669
Mestroni, Luisa; Begay, Rene L; Graw, Sharon L; Taylor, Matthew R G
Novel medical approaches and personalized medicine seek to use genetic information to 'individualize' and improve diagnosis, prevention, and therapy. The personalized management of cardiovascular disease involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenetics, in which individual genetic information is used to optimize the pharmacological treatments. Evidence suggests that the common polymorphic variants of modifier genes could influence drug response in cardiovascular disease in a variety of areas, including heart failure, arrhythmias, dyslipidemia, and hypertension. In heart failure, common genetic variants of β-adrenergic receptors, α-adrenergic receptors, and endothelin receptors (among others) have been associated with variable response to heart failure therapies. The challenge remains to develop strategies to leverage this information in ways that personalize and optimize cardiovascular therapy based on a patient's genetic profile. Although advances in technologies will continue to transition personalized medicine from the research to the clinical setting, healthcare providers will need to reshape the clinical diagnostic paradigms. Ultimately, pharmacogenetics will give providers the options for improving patient management on the basis of pharmacogenetic data.
Crist, Richard C.; Berrettini, Wade H.
Pharmacogenetic research has the potential to explain the variation in treatment efficacy within patient populations. Understanding the interaction between genetic variation and medications may provide a method for matching patients to the most effective therapeutic options and improving overall patient outcomes. The OPRM1 gene has been a target of interest in a large number of pharmacogenetic studies due to its genetic and structural variation, as well as the role of opioid receptors in a variety of disorders. The mu-opioid receptor (MOR), encoded by OPRM1, naturally regulates the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic variants in OPRM1, particularly the nonsynonymous polymorphism A118G, have been repeatedly associated with the efficacy of treatments for pain and various types of dependence. This review focuses on the current understanding of the pharmacogenetic impact of OPMR1, primarily in regards to the treatment of pain and addiction. PMID:24201053
Katsanos, Konstantinos H; Papadakis, Konstantinos A
Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data.
Myburgh, Renier; Hochfeld, Warren E; Dodgen, Tyren M; Ker, James; Pepper, Michael S
Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.
This review paper starts from discussing two models of network research: one starting from general networks, the other starting from the Ego. Ego based researches are characterized starting form the model of Dunbar as presenting networks of different size and intimacy, both in real and virtual networks. Researches into the personality determinants of networks mainly shows the effects of extroversion. The future of network research indicates a trend towards relating personal, conceptual, and neural networks.
Haas, David M
Pharmacogenetics as a tool to aid clinicians implement individualized pharmacotherapy is utilized in some areas of medicine. Pharmacogenetics in pregnancy is still a developing field. However, there are several areas of obstetric therapeutics where data are emerging that give glimpses into future therapeutic possibilities. These include opioid pain management, antihypertensive therapy, antidepressant medications, preterm labor tocolytics, antenatal corticosteroids and drugs for nausea and vomiting of pregnancy, to name a few. More data are needed to populate the therapeutic models and to truly determine if pharmacogenetics will aid in individualizing pharmacotherapy in pregnancy. The objective of this review is to summarize current data and highlight research needs.
Yang, Yao; Peter, Inga; Scott, Stuart A.
Spanning over 2000 years, the Jewish population has a long history of migration, population bottlenecks, expansions, and geographical isolation, which has resulted in a unique genetic architecture among the Jewish people. As such, many Mendelian disease genes and founder mutations for autosomal recessive diseases have been discovered in several Jewish groups, which have prompted recent genomic studies in the Jewish population on common disease susceptibility and other complex traits. Although few studies on the genetic determinants of drug response variability have been reported in the Jewish population, a number of unique pharmacogenetic variants have been discovered that are more common in Jewish populations than in other major racial groups. Notable examples identified in the Ashkenazi Jewish (AJ) population include the vitamin K epoxide reductase complex subunit 1 (VKORC1) c.106G>T (p.D36Y) variant associated with high warfarin dosing requirements and the recently reported cytochrome P450 2C19 (CYP2C19) allele, CYP2C19*4B, that harbors both loss-of-function [*4 (c.1A>G)] and increased-function [*17 (c.−806C>T)] variants on the same haplotype. These data are encouraging in that like other ethnicities and subpopulations, the Jewish population likely harbors numerous pharmacogenetic variants that are uncommon or absent in other larger racial groups and ethnicities. In addition to unique variants, common multi-ethnic variants in key drug metabolism genes (e.g., ABCB1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, NAT2) have also been detected in the AJ and other Jewish groups. This review aims to summarize the currently available pharmacogenetics literature and discuss future directions for related research with this unique population. PMID:24867283
Maroñas, Olalla; Latorre, Ana; Dopazo, Joaquín; Pirmohamed, Munir; Rodríguez-Antona, Cristina; Siest, Gérard; Carracedo, Ángel; LLerena, Adrián
Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.
Roederer, Mary W; Sanchez-Giron, Francisco; Kalideen, Kusha; Kudzi, William; McLeod, Howard L; Zhang, Wei
The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.
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Zineh, Issam; Pebanco, Glenn D; Aquilante, Christina L; Gerhard, Tobias; Beitelshees, Amber L; Beasley, Bach Nhi; Hartzema, Abraham G
Despite growing numbers of pharmacogenetics studies, little pharmacogenetics-based prescribing information is available to practitioners. It is possible that the lack of prescribing data for commonly used drugs is due to a paucity of evidence-based pharmacogenetics literature for these agents. To investigate the relationship between pharmacogenetics prescribing data in drug package inserts (PIs) and pharmacogenetics research literature for agents represented in the top 200 prescribed drugs for 2003. A PubMed search (to August 7, 2004) was performed to identify pharmacogenetics studies relevant to the top 200 drugs. These data were compared with PIs for drugs in the top 200 list that contained pharmacogenetics prescribing information. Pharmacogenetics data in the literature were available for 71.3% of the top 200 drugs. The gene involved coded for a drug-metabolizing enzyme in 34.5% of the literature sampled. The remaining 65.5% of the pharmacogenetics studies contained information largely related to genetic variability in target proteins and drug transporters. Three drugs with PIs containing pharmacogenetics prescribing information deemed to be useful to guide therapy were in the top 200 list (celecoxib, fluoxetine, pantoprazole). There was no consensus on the strength of association between genetic variability and drug response for these agents. The lack of specific pharmacogenetics-based prescribing information in PIs for commonly used drugs does not seem to be related to a paucity of pharmacogenetics data in the research literature. Rather, other factors including, but not limited to, the uncertain clinical relevance of genetic associations may make practical prescribing recommendations difficult.
Kudzi, W; Adjei, G O; Ofori-Adjei, D; Dodoo, A N O
Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.
Lötsch, Jörn; Geisslinger, Gerd
Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B1 (BDKRB1) and 5-HT1A (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information. PMID:20942817
Lötsch, Jörn; Geisslinger, Gerd
Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B(1) (BDKRB1) and 5-HT(1A) (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information.
Hedgecoe, Adam M
Most of the literature on pharmacogenetics assumes that the main problems in implementing the technology will be institutional ones (due to funding or regulation) and that although it involves genetic testing, the ethical issues involved in pharmacogenetics are different from, even less than, 'traditional' genetic testing. Very little attention has been paid to how clinicians will accept this technology, their attitudes towards it and how it will affect clinical practice. This paper presents results from interviews with clinicians who are beginning to use pharmacogenetics and explores how they view the ethics of pharmacogenetic testing, its use to exclude some patients from treatment, and how this kind of testing fits into broader debates around genetics. In particular this paper examines the attitudes of breast cancer and Alzheimer's disease specialists. The results of these interviews will be compared with the picture of pharmacogenetics painted in the published literature, as a way of rooting this somewhat speculative writing in clinical practice.
Drozda, Katarzyna; Labinov, Yana; Jiang, Ruixuan; Thomas, Margaret R; Wong, Shan S; Patel, Shitalben; Nutescu, Edith A; Cavallari, Larisa H
To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.
Sosa-Macias, Martha; Moya, Graciela E; LLerena, Adrián; Ramírez, Ronald; Terán, Enrique; Peñas-LLedó, Eva M; Tarazona-Santos, Eduardo; Galaviz-Hernández, Carlos; Céspedes-Garro, Carolina; Acosta, Hildaura
MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects.
Huang, R. Stephanie; Ratain, Mark J.
Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. PMID:19147868
Sosa-Macías, Martha; Teran, Enrique; Waters, William; Fors, Martha M; Altamirano, Catalina; Jung-Cook, Helgi; Galaviz-Hernández, Carlos; López-López, Marisol; Remírez, Diadelis; Moya, Graciela E; Hernández, Francisco; Fariñas, Humberto; Ramírez, Ronald; Céspedes-Garro, Carolina; Tarazona-Santos, Eduardo; LLerena, Adrián
Congress of Pharmacogenetics and Personalized Medicine. Ethnicity, clinical implementation and regulatory environment (MESTIFAR 2016 Quito). Quito, Ecuador, 19-21 May 2016. The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) was created in 2006 with the main aim of promoting personalized medicine and collaborative pharmacogenetics research in Spanish- and Portuguese-speaking countries in America and the Iberian Peninsula. The final goal of this initiative was the inclusion of Latin American populations that may benefit from the implementation of personalized medicine in drug therapy. Several initiatives have been promoted including the MESTIFAR project, which aimed to analyze the ethnicity, genotype and/or metabolic phenotype in Ibero-American populations. To date, 6060 healthy volunteers have been analyzed; among them, 2571 were admixed, 1824 were Caucasians, 1395 were Native Americans, 174 were Jews and 96 were Afro-descendants. Due to the large genetic variability within Latin Americans, ethnicity may be a relevant factor for the clinical implementation of personalized medicine. Moreover, the present status of clinical implementation and the future perspectives of pharmacogenetics, pharmacovigilance and clinical trials for drug regulation in Latin America compared with the EMA-Pharmacogenomics Working Party and the US FDA initiatives were analyzed.
Newman, W G
Pharmacogenetics, the study of genetic variation relevant to drug metabolism, is a rapidly evolving area of medicine. This brief review will consider some of the recent advances where inherited genetic variants have been associated with either drug efficacy or toxicity. Examples of where pharmacogenetic testing has been adopted into clinical practice will be provided as well as a look at its likely development over the next decade. Finally, the large increase in genetic testing of tumour tissue samples to predict response to molecularly targeted treatments in cancer will be considered.
Jones, Jermaine D; Comer, Sandra D; Kranzler, Henry R
Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects. This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD. Copyright © 2015 by the Research Society on Alcoholism.
Johnson, Julie A; Humma, Larisa M
Pharmacogenetics is a field aimed at understanding the genetic contribution to inter-patient variability in drug efficacy and toxicity. Treatment of cardiovascular disease is, in most cases, guided by evidence from well-controlled clinical trials. Given the solid scientific basis for the treatment of most cardiovascular diseases, it is common for patients with a given disease to be treated in essentially the same manner. Thus, the clinical trials have been very informative about treating large groups of patients with a given disease, but are slightly less informative about the treatment of individual patients. Pharmacogenetics and pharmacogenomics have the potential of taking the information derived from large clinical trials and further refining it to select the drugs with the greatest likelihood for benefit, and least likelihood for harm, in individual patients, based on their genetic make-up. In this paper, the current literature on cardiovascular pharmacogenetics is emphasised, and how the use of pharmacogenetic/pharmacogenomic information may be particularly useful in the future in the treatment of cardiovascular diseases is also highlighted.
Crews, Kristine R; Cross, Shane J; McCormick, John N; Baker, Donald K; Molinelli, Alejandro R; Mullins, Richard; Relling, Mary V; Hoffman, James M
The development and implementation of a pharmacist-managed clinical pharmacogenetics service are described. A pharmacist-managed clinical pharmacogenetics service was designed and implemented at an academic specialty hospital to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in the hospital's patients. A series of accredited educational seminars were conducted for our pharmacists to establish competencies in providing pharmacogenetic consults for the genes to be tested by the clinical pharmacogenetics service. The service was modeled after and integrated with an already-established clinical pharmacokinetics service. A steering committee was formed to evaluate the use of available tests, new evidence for implementation of additional tests, and other service quality metrics. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consultation. The consultation includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed. The service has been met with positive clinician feedback. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care. The development of and experience with a pharmacist-managed clinical pharmacogenetics service are described. The program's success has depended on collaboration between the clinical laboratory and pharmacists, and pharmacists' pharmacogenetic recommendations have been well accepted by prescribers.
Reprogenetics involves embryonic pre-implantation genetic diagnosis, provoking controversy over the creation of saviour siblings, eugenics and genetic enhancement. It will soon ascertain pharmacogenetic susceptibilities. Pharmacogenetics impacts upon public health initiatives underpinned by resource allocation constraints in that genetic epidemiological studies assist in administering health care resources and public health strategies. Knowing how likely sections of the population are to develop specific medical conditions so that lifestyle and environmental factors influencing these conditions can be targeted has the potential to save public money and improve public health. Aligning population groups with genetic susceptibilities with specific medications would enable cost-effective prescribing. Reprogenetics and pharmacogenetics also possess great commercial potential for nation states and biotechnology companies. Hence ethical legal safeguards for members of the public whose reproductive or genetic tissue is a research or health care resource are essential. Both legal measures such as informed consent and mechanisms for including the public in policy decisions over reprogenetics and pharmacogenetics must be rethought to ensure that they provide protection rather than function as rubber stamps which preclude deeper inquiry into justifications of projects.
Landau, R; Bollag, L A; Kraft, J C
Approximately 50 years ago, pharmacogenetics was described as a new field of medicine that may explain human drug action. Anaesthesia played a key role in the early investigations. An understanding of how a person's DNA influences drug metabolism and effectiveness may allow individually tailored prescriptions, improving outcomes and safety. The ultimate goal of pharmacogenetic research is to offer tailored personalised medicine to improve both the efficacy of medication and patient safety by helping to predict risk of adverse outcomes. In this review, we present a selection of historical landmarks where anaesthesia has been a catalyst for pharmacogenetic development. We examine the level of evidence and cite examples of candidate genes and common polymorphisms known to alter the response to peri-operative medication. Finally, we set forth current views and potential exciting perspectives that may arise from the application of pharmacogenetics to the daily practice of anaesthesia and pain medicine.
Houwink, Elisa J F; Rigter, Tessel; Swen, Jesse J; Cornel, Martina C; Kienhuis, Anne; Rodenburg, Wendy; Weda, Marjolein
Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care.
Aston-Jones, Gary; Deisseroth, Karl
Optogenetics with microbial opsin genes, and pharmacogenetics with designer receptors, represent potent and versatile experimental modalities that can be integrated with each other as well as with a rich diversity of synergistic methods to provide fundamental opportunities in neuroscience research. Since initial steps were taken with these approaches less than 10 years ago, we are witnessing a rapid rise in publications (Fig. 1). The 7th Annual Brain Research Meeting in New Orleans in October 2012, Optogenetics and Pharmacogenetics in Neuronal Function and Dysfunction, brought together leading researchers that have developed and used these tools to explore a wide range of questions in nervous system function and dysfunction. This special issue of Brain Research includes articles by speakers in this meeting and others, which together synthesize and summarize the state of the art for optogenetics and designer receptors. PMID:23422677
Aston-Jones, Gary; Deisseroth, Karl
Optogenetics with microbial opsin genes, and pharmacogenetics with designer receptors, represent potent and versatile experimental modalities that can be integrated with each other as well as with a rich diversity of synergistic methods to provide fundamental opportunities in neuroscience research. The 7th Annual Brain Research Meeting in New Orleans in October 2012, Optogenetics and Pharmacogenetics in Neuronal Function and Dysfunction, brought together leading researchers that have developed and used these tools to explore a wide range of questions in nervous system function and dysfunction. This special issue of Brain Research includes articles by speakers in this meeting and others, which together synthesize and summarize the state of the art for optogenetics and designer receptors. This article is part of a Special Issue entitled Optogenetics (7th BRES). Copyright © 2013 Elsevier B.V. All rights reserved.
Phillips, Elizabeth J; Mallal, Simon A
Drug hypersensitivity reactions and severe cutaneous adverse drug reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, are examples of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that could traditionally not have been predicted based on the pharmacological characteristics of the drug alone. The discovery of new associations between these syndromes and specific HLA has created the promise that risk for these reactions could be predicted through pharmacogenetic screening, thereby avoiding serious morbidity and mortality associated with these types of drug reactions. Despite this, several hurdles exist in the translation of these associations into pharmacogenetic tests that could be routinely used in the clinical setting. HLA-B*5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world. PMID:20602616
Reynolds, Gavin P; Templeman, Lucy A; Godlewska, Beata R
There is substantial unexplained interindividual variability in the drug treatment of schizophrenia. A substantial proportion of patients respond inadequately to antipsychotic drugs, and many experience limiting side effects. As genetic factors are likely to contribute to this variability, the pharmacogenetics of schizophrenia has attracted substantial effort. The approaches have mainly been limited to association studies of polymorphisms in candidate genes, which have been indicated by the pharmacology of antipsychotic drugs. Although some advances have been made, particularly in understanding the pharmacogenetics of some limiting side effects, genetic prediction of symptom response remains elusive. Nevertheless, with improvements in defining the response phenotype in carefully assessed and homogeneous subject groups, the near future is likely to see the identification of genetic predictors of outcome that may inform the choice of pharmacotherapy.
Russo, Giovanna; Gubbay, Anthony; Branford, Ruth; Sato, Hiroe
Summary points • Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. • Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. • While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). • Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. • This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain. PMID:26516523
Scott, Stuart A.
Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing. PMID:22095251
McMahon, Teresa; Tucci, Joseph
Objective This study aimed to explore how well Victorian pharmacists perceived they understood pharmacogenetics, their perceived capacity to counsel a patient about such testing, how they believed pharmacogenetics would impact upon their profession, and to investigate the ways in which Victorian pharmacists would like to be educated about pharmacogenetics. Methods A cross-sectional survey was dispatched to 800 Victorian pharmacists. The participants were randomly selected and the survey was anonymous. The survey contained questions about where the pharmacists worked, the pharmacists’ perceived knowledge of pharmacogenetics, how well they believed they would be able to counsel patients about pharmacogenetic testing, how they thought pharmacists should be educated on the topic and how they believed pharmacogenetics would impact upon their profession. Results 291 surveys were returned (36% response rate). Results suggest that Victorian pharmacists generally perceived they had a poor understanding of pharmacogenetics and that those who have more recently graduated from tertiary education had a better perceived understanding than those who have been in the workforce for longer. Most pharmacists indicated that they did not believe that they could counsel a patient adequately about the results of a pharmacogenetic test. Regarding education about pharmacogenetics, participants suggested that this would be best delivered during tertiary studies, and as seminars and workshops forming part of their continuing professional development. Although some pharmacists were unsure how pharmacogenetics would affect their profession, many believed it would have a major impact upon their role as a pharmacist and lead to improved patient care. Some concerns about the implementation of pharmacogenetics were noted, including economic and ethical issues. Conclusions This study highlights the need for further research across the pharmacy profession in Australia on the issue of preparedness
Boessen, Ruud; van der Baan, Frederieke; Groenwold, Rolf; Egberts, Antoine; Klungel, Olaf; Grobbee, Diederick; Knol, Mirjam; Roes, Kit
Two-stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two-stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family-wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed 'true' subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two-stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design.
Haidar, Cyrine E; Hoffman, James M; Gammal, Roseann S; Relling, Mary V; Crews, Kristine R
The structure and development of an innovative, ASHP-accredited postgraduate year 2 (PGY2) clinical pharmacogenetics residency program are described. A 12-month PGY2 clinical pharmacogenetics residency was created at St. Jude Children's Research Hospital in accordance with the ASHP standards for advanced practice residencies. The purpose of this 12-month residency program is to prepare pharmacy residents to implement pharmacogenetics in clinical practice. The program helps residents develop expertise in the science of pharmacogenetics as well as an understanding of translational research, innovative pharmacy practice model development, and clinical informatics. The resident learns to optimize patient outcomes through the expert provision of evidence-based, patient-centered precision medicine as an integral part of an interprofessional team. After completing the program, residents are expected to have the clinical skills necessary to practice in the field of clinical pharmacogenetics and independently implement pharmacogenetic testing in other health-system settings. Because implementation of pharmacogenetics requires collaboration across many disciplines, residents works within an interprofessional team of physicians, nurses, informatics specialists, pharmacists, and clinical laboratory personnel to achieve program goals. Since the first resident graduated in 2012, the program has graduated 1 resident each year. Graduated residents have accepted pharmacogenetics positions at major academic medical centers and community hospitals, as well as academic and research positions with a pharmacogenetics emphasis. A PGY2 clinical pharmacogenetics residency was successfully developed at St. Jude in 2013. After completion of the program, residents are equipped with the clinical skills and necessary experience to drive precision medicine forward and lead the implementation of pharmacogenetic testing in other healthcare settings. Copyright © 2017 by the American Society of
Arias, Albert J; Sewell, R Andrew
Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D(4) receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject's age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.
Pouget, Jennie G; Shams, Tahireh A; Tiwari, Arun K; Müller, Daniel J
Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.
Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs. © 2017 John Wiley & Sons Ltd.
Pouget, Jennie G.; Shams, Tahireh A.; Tiwari, Arun K.; Müller, Daniel J.
Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h2~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. PMID:25733959
Szefler, Stanley J; Chinchilli, Vernon M; Israel, Elliot; Denlinger, Loren Clark; Lemanske, Robert F; Calhoun, William; Peters, Stephen P
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
Drozda, Katarzyna; Labinov, Yana; Jiang, Ruixuan; Thomas, Margaret R.; Wong, Shan S.; Patel, Shitalben; Nutescu, Edith A.
Objective. To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. Design. First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. Assessment. Students’, residents’, and fellows’ achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. Conclusion. A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics. PMID:24159216
Shah, Rashmi R
result in complex prescribing information. Genotype-specific dosing regimens will have to be more precise and marketing strategies more prudent. However, not all variations in drug responses are related to pharmacogenetic polymorphisms. Drug response can be modulated by a number of non-genetic factors, especially co-medications and presence of concurrent diseases. Inappropriate prescribing frequently compounds the complexity introduced by these two important non-genetic factors. Unless prescribers adhere to the prescribing information, much of the benefits of pharmacogenetics will be squandered. Discovering highly predictive genotype–phenotype associations during drug development and demonstrating their clinical validity and utility in well-designed prospective clinical trials will no doubt better define the role of pharmacogenetics in future clinical practice. In the meantime, prescribing should comply with the information provided while pharmacogenetic research is deservedly supported by all concerned but without unrealistic expectations. PMID:16096112
Sychev, D A; Malova, E U
For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers . On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" . A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia . But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs . To assess the extent of genetic testing use for improving use of medicines. PubMed and E-Library searches for the period of 2004-2015. The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing
WEITZEL, KRISTIN W.; ELSEY, AMANDA R.; LANGAEE, TAIMOUR Y.; BURKLEY, BENJAMIN; NESSL, DAVID R.; OBENG, ANIWAA OWUSU; STALEY, BENJAMIN J.; DONG, HUI-JIA; ALLAN, ROBERT W.; LIU, J. FELIX; COOPER-DEHOFF, RHONDA M.; ANDERSON, R. DAVID; CONLON, MICHAEL; CLARE-SALZLER, MICHAEL J.; NELSON, DAVID R.; JOHNSON, JULIE A.
Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine. PMID:24616371
Brandl, Eva J; Kennedy, James L; Müller, Daniel J
Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods: We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion: First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. PMID:24881126
Zhang, Jian-Ping; Malhotra, Anil K.
Importance of the field Antipsychotic drug is the mainstay of treatment for schizophrenia, and there are large inter-individual differences is clinical response and side effects. Pharmacogenetics provides a valuable tool to fulfill the promise of personalized medicine by tailoring treatment based on one's genetic markers. Areas covered in this review This article reviews the pharmacogenetic literature from early 1990s to 2010, focusing on two aspects of drug action: pharmacokinetics and pharmacodynamics. Genetic variants in the neurotransmitter receptors including dopamine and serotonin, and metabolic pathways of drugs including CYP2D6 and COMT, were discussed in association with clinical drug response and side effects. What the reader will gain Readers are expected to learn the up-to-date evidence in pharmacogenetic research, and to gain familiarity to the issues and challenges facing the field. Take home message Pharmacogenetic research of antipsychotic drugs is both promising and challenging. There is consistent evidence that some genetic variants can affect clinical response and side effects. However, more studies that are designed specifically to test pharmacogenetic hypotheses are clearly needed to advance the field. PMID:21162693
de Graaff, L C G; van Schaik, R H N; van Gelder, T
Taking into account the high frequency of adverse drug reactions (ADRs) in the clinic and taking into account the growing knowledge of the genetic mechanisms underlying some of these ADRs, we believe that every clinician should know at least the basic principles of pharmacogenetics. However, our experience is that many clinicians are unaware of the potential contribution of pharmacogenetic testing and have not implemented this new modality in their daily practice. We present a case of Stevens-Johnson syndrome in a patient treated with carbamazepine. Following the pathways of clinical reasoning, we describe the possibilities of pharmacogenetic testing in the clinic (HLA-B*1502 and HLA-A*3101 in our patient). We describe the pharmacological and pharmacogenetic aspects relevant for the clinician's daily practice (the existence of ADR subtypes, cytochrome P450, drug-drug interactions, genetic variations, CYP450 and HLA genotyping). Based on the Dutch top 100 of most prescribed drugs, we provide data on CYP450 and HLA genotypes relevant to those 100 most commonly used drugs. We discuss the availability and costs of pharmacogenetic testing, show a calculation of the 'number needed to genotype' and, based on these data, we propose a decision model for pharmacogenetic testing by clinicians.
Jiménez-Varo, Enrique; Cañadas-Garre, Marisa; Garcés-Robles, Víctor; Gutiérrez-Pimentel, María José; Calleja-Hernández, Miguel Ángel
Acenocoumarol (ACN) has a narrow therapeutic range that is especially difficult to control at the start of its administration. Various dosing pharmacogenetic-guided dosing algorithms have been developed, but further work on their external validation is required. The aim of this study was to evaluate the extrapolation of pharmacogenetic algorithms for ACN as an alternative to the development of a specific algorithm for a given population. The predictive performance, deviation, accuracy, and clinical significance of five pharmacogenetic algorithms (EU-PACT, Borobia, Rathore, Markatos, Krishna Kumar) were compared in 189 stable ACN patients representing all indications for anticoagulant treatment. The correlation between the dose predictions of the five pharmacogenetic models ranged from 7.7 to 70.6% and the percentage of patients with a correct prediction (deviation ≤20% from actual ACN dose) ranged from 5.9 to 40.7%. EU-PACT and Borobia pharmacogenetic dosing algorithms were the most accurate in our setting and evidenced the best clinical performance. Among the five models studied, the EU-PACT and Borobia pharmacogenetic dosing algorithms demonstrated the best potential for extrapolation. Copyright © 2015 Elsevier Inc. All rights reserved.
Although a number of antipsychotics have been introduced for the treatment of schizophrenia, inter-individual differences of in antipsychotic response and the number of refractory schizophrenic patients have become two of the most challenging problems in clinical psychiatry. Thus, the pharmacogenetics of antipsychotics have been aimed at providing genetic components of this inter-individual variability in antipsychotic response in order to establish an individually-based pharmacotherapy for schizophrenia and to elucidate the mechanism of antipsychotic response so as to solve the refractoriness of schizophrenia. Pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence can be divided into two categories: the genetic background of pharmacokinetics, i.e. the absorption, distribution, tissue localization, biotransformation and excretion of drugs, and pharmacodynamics, i.e. the biochemical and physiological consequences of a drug and its mechanism of action. Pharmacokinetics of antipsychotics has been focused mainly on the association between genetic polymorphisms in CYP genes, including CYP2D6, and the metabolism of these drugs. Polymorphism in CYP2D6 enables a division of individuals within a given population into at least two groups, i.e. poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) of certain drugs. PMs have higher plasma concentrations of and more adverse effects from antipsychotics. UMs could be one of the important factors that induce treatment-refractoriness to antipsychotics. Genetic polymorphisms in serotonin and dopamine receptors that have a high affinity for antipsychotics have so far been extensively investigated in the pharmacodynamics of this type of drug. Not just one gene but multiple genes play a role in complex phenotypes, including the clinical response to medication. Thus, a multiple candidate genes approach has recently been adopted in the
Eum, Seenae; Lee, Adam M.; Bishop, Jeffrey R.
Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed. PMID:27757066
Eum, Seenae; Lee, Adam M; Bishop, Jeffrey R
Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed.
Dulucq, Stéphanie; Krajinovic, Maja
Imatinib mesylate (IM), a tyrosine kinase inhibitor, is one of the first molecularly targeted therapies to have been used in the clinic. It has proven to be efficient in the treatment of chronic myeloid leukemia and also in other malignancies that involve expression of a tyrosine kinase. However, some patients can develop resistance and others suffer from toxic side effects. The pharmacokinetics of IM depends on several enzymes and transporters, and several studies have attempted to identify genetic factors associated with variable drug levels and clinical responses using a candidate gene approach. Larger and more homogenous studies are still needed to replicate the findings obtained so far, or to analyze other genetic variations to get clearer insights into how IM treatment can be tailored to each patient's genetics. Here we summarize pharmacogenetic studies of IM and highlight the genetic markers that could be used to improve the treatment and management of diseases for which IM is used.
Imatinib mesylate (IM), a tyrosine kinase inhibitor, is one of the first molecularly targeted therapies to have been used in the clinic. It has proven to be efficient in the treatment of chronic myeloid leukemia and also in other malignancies that involve expression of a tyrosine kinase. However, some patients can develop resistance and others suffer from toxic side effects. The pharmacokinetics of IM depends on several enzymes and transporters, and several studies have attempted to identify genetic factors associated with variable drug levels and clinical responses using a candidate gene approach. Larger and more homogenous studies are still needed to replicate the findings obtained so far, or to analyze other genetic variations to get clearer insights into how IM treatment can be tailored to each patient's genetics. Here we summarize pharmacogenetic studies of IM and highlight the genetic markers that could be used to improve the treatment and management of diseases for which IM is used. PMID:21122163
Weitzel, Kristin W; Cavallari, Larisa H; Lesko, Lawrence J
While recent discoveries have paved the way for the use of genotype-guided prescribing in some clinical environments, significant debate persists among clinicians and researchers about the optimal approach to pharmacogenetic testing in clinical practice. One crucial factor in this debate surrounds the timing and methodology of genotyping, specifically whether genotyping should be performed reactively for targeted genes when a single drug is prescribed, or preemptively using a panel-based approach prior to drug prescribing. While early clinical models that employed a preemptive approach were largely developed in academic health centers through multidisciplinary efforts, increasing examples of pharmacogenetic testing are emerging in community-based and primary care practice environments. However, educational and practice-based resources for these clinicians remain largely nonexistent. As such, there is a need for the health care system to shift its focus from debating about preemptive genotyping to developing and disseminating needed resources to equip frontline clinicians for clinical implementation of pharmacogenetics. Providing tools and guidance to support these emerging models of care will be essential to support the thoughtful, evidence-based use of pharmacogenetic information in diverse clinical practice environments. Specifically, the creation of efficient and accurate point-of-care resources, practice-based tools, and clinical models is needed, along with identification and dissemination of sustainable avenues for pharmacogenetic test reimbursement.
Soong, Richie; Diasio, Robert B
In cancer pharmacogenetics (the study of how variability in a single or set of known genes influences drug response) and pharmacogenomics (the study of variability on a genome-wide scale), one of the most important fields of research focuses on the fluoropyrimdines (FPs) and, in particular, 5-fluorouracil (5-FU). After over 40 years of use, FPs remain one of the most commonly used cancer chemotherapy agents and their application includes a wide spectrum of cancer types. FPs also continue to be the baseline component for many new regimens with novel molecular-targeted agents that are being rapidly introduced. Hence, it would seem appropriate that pharmacogenetic/genomic models for optimizing cancer patient management would involve indicators of FP response. In this article, the current trends in FP pharmacogenetics and pharmacogenomics are reviewed based on the advances made to date and the challenges faced in realizing their full potential.
Crews, Kristine R.; Cross, Shane J.; McCormick, John N.; Baker, Donald K.; Molinelli, Alejandro R.; Mullins, Richard; Relling, Mary V.; Hoffman, James M.
Purpose The development and implementation of a pharmacist-managed Clinical Pharmacogenetics service is described. Summary Therapeutic drug monitoring (TDM) is a well-accepted role of the pharmacist. Pharmacogenetics, the study of genetic factors that influence the variability in drug response among patients, is a rapidly evolving discipline that integrates knowledge of pharmacokinetics and pharmacodynamics with modern advances in genetic testing. There is growing evidence for the clinical utility of pharmacogenetics, and pharmacists can play an essential role in the thoughtful application of pharmacogenetics to patient care. A pharmacist-managed Clinical Pharmacogenetics service was designed and implemented. The goal of the service is to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in our patients. The service is modeled after and integrated with an already established Clinical Pharmacokinetics service. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consult. The consult includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed, consisting of 66 TPMT tests, 65 CYP2D6 tests, and 5 UGT1A1 tests. Our service has been met with positive clinician feedback. Conclusion Our experience demonstrates the feasibility of the design and function of a pharmacist-managed Clinical Pharmacogenetics service at an academic specialty hospital. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care, thereby potentially improving patient outcomes. PMID:21200062
Chen, Suning; Zhou, Jie; Xi, Miaomiao; Jia, Yanyan; Wong, Yan; Zhao, Jinyi; Ding, Likun; Zhang, Jian; Wen, Aidong
Diabetes is a major health problem worldwide, and metformin, a traditional oral anti-hyperglycemic drug, is now believed to be the most widely prescribed antidiabetic drug. Metformin acts primarily by inhibiting hepatic glucose production and improving insulin sensitivity. Metformin is absorbed predominately by the small intestine and excreted in an unaltered form in the urine. The pharmacokinetics of metformin is primarily determined by membrane transporters, including the plasma membrane monoamine transporter (PMAT), the organic cation transporters (OCTs), the multidrug and toxin extrusion (MATE) transporters, and the critical protein kinase AMPactivated protein kinase (AMPK). PMAT may play a role in the uptake of metformin from the gastrointestinal tract, while OCTs mediate the intestinal absorption, hepatic uptake, and renal excretion of metformin. MATEs are believed to contribute to the hepatic and renal excretion of the drug. The pharmacologic effects of metformin are primarily exerted in the liver, at least partly via the activation of AMPK and the subsequent inhibition of gluconeogenesis. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Moreover, it has become increasingly clear that membrane transporters are important determinants of the pharmacokinetics of metformin. In this review, we will discuss the genetic variants of major transporters that purportedly determine the pharmacokinetics of metformin in terms of drug bioavailability, distribution, and excretion, such as PMAT, OCTs, and MATEs. Understanding how genetic variation affects metformin response will help promote more effective use of the drug for the treatment of type 2 diabetes (T2D).
Almomani, Basima; Hawwa, Ahmed F; Goodfellow, Nicola A; Millership, Jeffrey S; McElnay, James C
Pharmacogenetics is a rapidly growing field that aims to identify the genes that influence drug response. This science can be used as a powerful tool to tailor drug treatment to the genetic makeup of individuals. The present study explores the coverage of the topic of pharmacogenetics and its potential benefit in personalised medicine by the UK newsprint media. The LexisNexis database was used to identify and retrieve full text articles from the 10 highest circulation national daily newspapers and their Sunday equivalents in the UK. Content analysis of newspaper articles which referenced pharmacogenetic testing was carried out. A second researcher coded a random sample (21%) of newspaper articles to establish the inter-rater reliability of coding. Of the 256 articles captured by the search terms, 96 articles (with pharmacogenetics as a major component) met the study inclusion criteria. The majority of articles over-stated the benefits of pharmacogenetic testing while paying less attention to the associated risks. Overall beneficial effects were mentioned 5.3 times more frequently than risks (p < 0.001). The most common illnesses for which pharmacogenetically based personalised medicine was discussed were cancer, cardiovascular disease and CNS diseases. Only 13% of newspaper articles that cited a specific scientific study mentioned this link in the article. There was a positive correlation between the size of the article and both the number of benefits and risks stated (P < 0.01). More comprehensive coverage of the area of personalised medicine within the print media is needed to inform public debate on the inclusion of pharmacogentic testing in routine practice.
Lima, John J.; Blake, Kathryn V.; Tantisira, Kelan G.; Weiss, Scott T.
Purpose of review Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs. Recent findings Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers. Summary Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine. PMID:19077707
Almeida-Gutiérrez, Eduardo; Paniagua, Ramón; Furuya, María ElenaYuriko
In order to increase the research in important health questions at a national and institutional levels, the Human Papillomavirus Research Network of the Health Research Coordination of the Instituto Mexicano del Seguro Social offers this supplement with the purpose of assisting patients that daily look for attention due to the human papillomavirus or to cervical cancer.
Pharmacogenetic (PGx) testing has the potential to improve drug therapy in an individual by informing appropriate drug dosing or drug selection in order to maximize efficacy and safety. Although multiple studies have illustrated the potential benefits of such testing when applied to specific drugs across a broad range of therapy areas, the uptake of PGx testing in routine clinical practice has been relatively limited. Implementation appears to be hampered by the absence of sufficiently strong evidence linking the results of testing with actionable benefits in terms of clinical outcomes. Meanwhile, there are now adequate data to allow dosing recommendations as have been developed by bodies including the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) in several settings, including TPMT/thiopurines, CYP2C19/clopidogrel, CYP2D6/codeine, VKORC1-CYP2C9/warfarin, HLA-B*5701/abacavir, SLCO1B1/simvastatin and HLAB*5801/allopurinol. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) have also recently initiated surveys in order to better understand the extent of, and the role played by, PGx testing in clinical practice. This should help identify where further training and education may be beneficial. To this end, in collaboration with ESPT, the IFCC Pharmacogenetic Laboratory Network has now been formed, with the aim of improving the uptake and quality of PGx testing. PMID:27683445
Shin, Jaekyu; Johnson, Julie A.
β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770
munication (both satellite and ground radio channels) provides a solution. 4\\^ ;o is a multi-access broadcast medium. A signal generated by a radio...transmit signals over the same channel. (This is the multi-access capability.) Hence, a single ground radio channel provides a completely connected...network topology for a large number However, if two signals (packet transmissions) at the same carrier frequency overlap in time at a radio receiver, we
Hoffman, James M.; Gammal, Roseann S.; Relling, Mary V.; Crews, Kristine R.
Purpose The structure and development of an innovative clinical pharmacogenetics post-graduate year 2 (PGY2) ASHP-accredited residency program is described. Summary The advent of the era of genomics has left practitioners wondering how to interpret the data obtained from sequencing and genotyping patients. In order to train the next leaders in the area of implementing pharmacogenetics, St. Jude Children’s Research Hospital established the first accredited residency program in clinical pharmacogenetics. The 12-month long PGY2 residency was created in accordance with the ASHP standards for advanced practice residencies. The resident learns to optimize patient outcomes through the expert provision of evidence-based, patient-centered precision medicine as an integral part of an interdisciplinary team. The resident gains hands-on experience in a dynamic environment regarding all aspects of running a clinical pharmacogenetics service. Since the first resident graduated in 2012, the program has graduated one resident each year. Conclusion To fill a need for pharmacists trained in pharmacogenetics, an innovative PGY2 residency in clinical pharmacogenetics was successfully developed. Upon completion of the program, residents are equipped with the clinical skills and necessary experience to drive precision medicine forward and lead the implementation of pharmacogenetics in various healthcare settings. PMID:28274984
Fenton, Evelyn; Harvey, Janet; Sturt, Jackie
This paper presents a conceptual framework and tool kit, generated from the evaluation of five primary care research networks (PCRNs) funded by the then London, National Health Service (NHS) Executive. We employed qualitative methods designed to match the most important characteristics of PCRNs, conducting five contextualized case studies covering the five networks. A conceptual evaluation framework based on a review of the organization science literature was developed and comprised the broad, but inter-related organizational dimensions of structure, processes, boundaries and network self-evaluation as input factors and strategic emphasis as epitomized by network objectives. These dimensions were comprised of more detailed subdimensions designed to capture the potential of the networks to create ideas and knowledge, or intellectual capital, the key construct upon which our evaluation tool kit was based. We considered the congruence, or fit, between network objectives and input factors: greater congruence implied greater ability to achieve implicit and overt objectives. We conclude that network evaluation must take place, over time, recognizing stage of development and potential for long-term viability, but within a generic framework of inputs and outputs. If there is a good fit or congruence between their input factors and network objectives, networks will be internally coherent and able to operate at optimum effectiveness.
Amitai, Maya; Kronenberg, Sefi; Cohen, Tali; Frisch, Amos; Weizman, Abraham; Apter, Alan
Anxiety disorders are chronic disorders appearing with a high frequency in the general population and causing much distress to those suffering from them. The current common treatment consists of antidepressants, primarily from the serotonin-selective-reuptake-inhibitor (SSRI) class. However, despite the relative effectiveness of these medications the patients' responses vary widely with one third not responding at all. While we do not currently have the ability to predict who will respond positively to the medication, it is hoped that genetic research will make it possible to prospectively identify responders and thus help avoid failed treatment attempts and side-effects. The field of pharmacogenetics is divided into pharmaco-kinetics (genetic factors that influence the drug metabolism in the body) and pharmco-dynamics (genetic factors that affect the response to the drug at the level of the receptors/transporters/enzymes in the target organs). Contrary to the treatment of depression, there is little research available on the pharmacogenetics of anxiety disorders and the existing research coincides with the studies on depression. The primary pharmacogenetic-dynamic findings are related to serotonergic genes of which those with the long allele of the serotonin transporter gene (5-HTTLPR) are expected to respond positively to treatment, and the same is true regarding genetic variants of several serotonin receptors. The pharmacogenetic-kinetic findings focus on the CYP450 enzyme system. The hope is that with the progression of the pharmacogenetic research new genetic variants will be discovered which, when combined with the clinical characteristics of those suffering from anxiety disorders, will enable the development of novel treatment algorithms to be customized for each patient.
Meeks, Eric; Turner, Brian; Chatterjee, Anirvan; Yuan, Leslie
In 2009, UCSF embarked on a journey to utilize industry-backed application standards to extend our research networking tool of choice, Profiles, into a software platform. The goal of this work was to bring extended data and functionality to our researchers' online environment and make it easier to share independently-developed software innovations with others. We used the OpenSocial standard to achieve these ends. In 2012 we extended the OpenSocial standard to support RDF and the VIVO Ontology in an effort titled "Open Research Network Gadgets" or ORNG. Our work has been adopted by two major academic open source research networking tools - Harvard Catalyst Profiles and VIVO, and the ORNG standard is now available for use by the 50+ institutions that use recent versions of the two software products.
Richard Weinshilboum has a no-nonsense attitude about pharmacogenetics. He is enthusiastic about the practicalities and ramifications of the field's solid accomplishments, but he carefully measures statements that might feed the hype that is en courant about the brave new postgenomic world of drug therapy. Although the terms "pharmacogenomics" and "pharmacogenetics" are often used interchangeably (a linguistic quirk to which Weinshilboum does not object), he consistently avoids the latter, perhaps more glitzy, word. Weinshilboum has spent over thirty years as a clinical pharmacologist, exploring in particular the variability of drug metabolism that occurs among patients as a function of their genetic constitution. The research efforts from his line of work have materialized into clinical application and have helped to set the stage for the individualization of drug treatment according to each patient's genetic constitution-not yet on the genomewide scale that Weinshilboum enthusiastically foresees, but certainly as pertains to multiple genes and drugs for any given patient. The interview with Weinshilboum occurred at this year's annual meeting of ASPET, at which he was conferred the Harry Gold Award in Clinical Pharmacology.
Cascorbi, Ingolf; Werk, Anneke Nina
Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed. Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.
After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signalling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3, CREB, and Na+-K+ ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment. PMID:25687772
After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na(+)-K(+) ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment.
Bruce J. West Social Sciences Distributed Algorithms for Learning and Cognitive Medium Access with Logarithmic Regret...the traditional physical sciences, social sciences, life sciences, and information sciences. No one discipline or collection of disciplines can...pathologies encountered by the Warfighter. Exploration of cooperative behavior of social networks, such as swarms, is a significant research
Froehlich, Tanya E.; McGough, James J.; Stein, Mark A.
One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments. PMID:20088618
Murphy, Brandon F.
This paper will focus the on research and testing done on penetrating a network for security purposes. This research will provide the IT security office new methods of attacks across and against a company's network as well as introduce them to new platforms and software that can be used to better assist with protecting against such attacks. Throughout this paper testing and research has been done on two different Linux based operating systems, for attacking and compromising a Windows based host computer. Backtrack 5 and BlackBuntu (Linux based penetration testing operating systems) are two different "attacker'' computers that will attempt to plant viruses and or NASA USRP - Internship Final Report exploits on a host Windows 7 operating system, as well as try to retrieve information from the host. On each Linux OS (Backtrack 5 and BlackBuntu) there is penetration testing software which provides the necessary tools to create exploits that can compromise a windows system as well as other operating systems. This paper will focus on two main methods of deploying exploits 1 onto a host computer in order to retrieve information from a compromised system. One method of deployment for an exploit that was tested is known as a "social engineering" exploit. This type of method requires interaction from unsuspecting user. With this user interaction, a deployed exploit may allow a malicious user to gain access to the unsuspecting user's computer as well as the network that such computer is connected to. Due to more advance security setting and antivirus protection and detection, this method is easily identified and defended against. The second method of exploit deployment is the method mainly focused upon within this paper. This method required extensive research on the best way to compromise a security enabled protected network. Once a network has been compromised, then any and all devices connected to such network has the potential to be compromised as well. With a compromised
Guzman, A K; Ding, M; Xie, Y; Martin, K A
As the prevalence and severity of obesity and its complications have risen significantly in worldwide populations, behavioral interventions alone have been inconsistent in promoting sufficient, sustained weight loss. Consequently, there has been intense interest in the development of anti-obesity medications as treatment strategies. When coupled with structured lifestyle modifications, pharmacotherapy can enhance weight loss. While less efficacious than bariatric surgery, drug therapy may be an alternative to surgery for some obese patients, and is an emerging strategy for weight maintenance. The goal of pharmacogenetics is to help identify patients who will benefit most from drug therapies while minimizing the risk of adverse effects. In this review, we summarize the pharmacogenetic literature on obesity drugs of the past (sibutramine, rimonabant), present (orlistat, lorcaserin, phentermine, topiramate), and future (buprioprion/naltrexone).
Szekanecz, Zoltán; Meskó, Bertalan; Poliska, Szilard; Váncsa, Andrea; Szamosi, Szilvia; Végh, Edit; Simkovics, Enikö; Laki, Judit; Kurkó, Júlia; Besenyei, Timea; Mikecz, Katalin; Glant, Tibor T.; Nagy, László
Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, DMARDs and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of NSAIDs, cortisosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics, however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology. PMID:23564183
Szekanecz, Zoltán; Meskó, Bertalan; Poliska, Szilard; Váncsa, Andrea; Szamosi, Szilvia; Végh, Edit; Simkovics, Enikö; Laki, Judit; Kurkó, Júlia; Besenyei, Timea; Mikecz, Katalin; Glant, Tibor T; Nagy, László
Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs) and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of non-steroidal anti-inflammatory drugs, corticosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics; however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes, may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology.
Zeidler, E M; Goetz, A E; Zöllner, C
Pharmacogenetics deals with hereditary factors which influence the pharmacodynamics and pharmacokinetics of drugs leading to individual diverse reactions. Also in anesthesiology differences in the pharmacogenetics of patients can lead to relevant alterations in the pharmacodynamics of drugs. This article provides a summary of polymorphisms relevant to commonly used anesthetic agents and the clinical relevance in patients treated with these compounds. It describes the possibilities, the problems and limits of pharmacogenetic diagnostics and therapy and explains how this follows the target of individualized medicine. This article describes in detail the alterations in pharmacodynamics and pharmakokinetics relevant for anesthesia and their clinical significance. Based on the results of current studies, an overview of the most important drugs in anesthesiology with significant polymorphisms is given. These include opioids, muscle relaxants, volatile anesthetic agents, non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, antiemetics and cardiovascular drugs as well as platelet aggregation inhibitors, anticoagulants and the so-called new oral anticoagulants. Genetic alterations can lead to substantial modifications in the effectiveness of drugs. Genetic alterations of opioid receptors and the enzyme cytochrome P450 (CYP) 2D6 can result in a failure of analgesia after administration of opioids. Alterations in plasma cholinesterase activity are associated with a prolonged effectiveness of muscle relaxants. Polymorphisms in ryanodine receptors can contribute to the development of the feared MH in patients after administration of volatile anesthetics or succinylcholine. The study results presented here emphasize that these days knowledge on pharmacogenetics should not be missing in modern induction of anesthesia. In the future a blood sample could enable physicians to identify pharmacologically relevant markers. And these could guide the decision on the
Haile, Colin N.; Kosten, Thomas R.; Kosten, Therese A.
Background Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders. Objectives To review how genetic variation affects responses to cocaine, amphetamine, and methamphetamine and how this information may guide pharmacotherapy. Methods We performed a cross-referenced literature search on pharmacogenetics, cocaine, amphetamine, and methamphetamine. Results We describe functional genetic variants for enzymes dopamine-beta-hydroxylase (DβH), catechol-O-methyltransferase (COMT), and dopamine transporter (DAT1), dopamine D4 receptor, and brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP; C-1021T) in the DβH gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction. Individuals with variable number tandem repeats (VNTR) of the SLC6A3 gene 3′-untranslated region polymorphism of DAT1 have altered responses to drugs. The 10/10 repeat respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant show blunted euphoria and physiological response to amphetamine. COMT, D4 receptor, and BDNF polymorphisms are linked to methamphetamine abuse and psychosis. Conclusions Disulfiram and methylphenidate pharmacotherapies for cocaine addiction are optimized by considering polymorphisms affecting DβH and DAT1 respectively. Altered subjective effects for amphetamine in DAT1 VNTR variants suggest a ‘protected’ phenotype. Scientific Significance Pharmacogenetic-based treatments for psychostimulant addiction are critical for successful treatment. PMID:19462300
The USDA ARS Research Unit based at the Jornada Experimental Range outside of Las Cruces, NM, is a member of the USDA’s Long Term Agro-ecosystem Research (LTAR) Network, the National Science Foundation’s Long Term Ecological Research (LTER) Network, the National Ecological Observation Network (NEON)...
Lubomirov, Rubin; Telenti, Amalio; Rotger, Margalida
Pharmacogenetics, the study of how individual genetic profiles influence the response to drugs, is an important topic. Results from pharmacogenetics studies in various clinical settings may lead to personalized medicine. Herein, we present the most important concepts of this discipline, as well as currently-used study methods.
In July 1993, the Canopy Research Network was established with a 2-year planning grant from the National Science Foundation to bring together forest canopy researchers, quantitative scientists, and computer specialists to establish methods for collecting, storing, analyzing, interpreting, and displaying three-dimensional data that relate to tree crowns and forest canopies. The CRN is now soliciting input from scientists in other fields who may have developed techniques and software to help obtain answers to questions that concern the complex three-dimensional structure of tree crowns and forest canopies. Over the next 3 years, the CRN plans to compile an array of research questions and issues requiring information on canopy structure, examine useful information models and software tools already in use in allied fields, and develop conceptual models and recommendations for the types and format of information and analyses necessary to answer research questions posed by canopy researchers.
Bradshaw, Elizabeth H
Third Annual Open Meeting of the UK Pharmacogenetics and Stratified Medicine Network 14 January 2015, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK The third Annual Open Meeting of the UK Pharmacogenetics and Stratified Medicine Network was held on 14 January 2015 in association with the Wellcome Trust on the Wellcome Trust Genome Campus at Hinxton, Cambridge, UK. In the morning, speakers from Cancer Research UK, the Medical Research Council, Genomics England, Innovate UK (formerly TSB) and the Department of Health described the current major projects they are funding. In the afternoon, speakers from various universities around the United Kingdom presented data on pharmacogenetics and stratified medicine research covering diverse disease areas including cancers, warfarin dosing, Gaucher disease and rheumatoid arthritis.
Pharmacogenetics seeks to elucidate the variations in individual's genetic sequences in order to better understand the differences seen in pharmacokinetics, drug metabolism, and efficacy between patients. This area of research is rapidly accelerating, aided by the use of novel and more economical molecular technologies. A substantial evidence base is being generated with the hopes that in the future it may be used to generate personalised treatment regimens in order to improve patient comfort and safety and reduce incidences of morbidity and mortality. Anaesthetics is an area of particular interest in this field, with previous research leading to better informed practice, specifically with regards to pseudocholinesterase deficiency and malignant hyperthermia. In this review, recent pharmacogenetic data pertaining to anaesthetic drugs will be presented and possible future applications and implications for practice will be discussed. PMID:26779337
Lacchini, Riccardo; Tanus-Santos, Jose E
Sildenafil and other PDE-5 inhibitors have revolutionized erectile dysfunction (ED) treatment. However, a significant number of patients do not respond or present adverse reactions to these drugs. While genetic polymorphisms may underlie this phenomenon, very little research has been undertaken in this research field. Most of the current knowledge is based on sildenafil, thus almost completely ignoring other important pharmacological therapies. Currently, the most promising genes with pharmacogenetic implications in ED are related to the nitric oxide and cGMP pathway, although other genes are likely to affect the responsiveness to treatment of ED. Nevertheless, the small number of studies available opens the possibility of further exploring other genes and phenotypes related to ED. This article provides a comprehensive overview of the genes being tested for their pharmacogenetic relevance in the therapy of ED.
Rego-Pérez, Ignacio; Fernández-Moreno, Mercedes; Blanco, Francisco J
Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown etiology with genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying antirheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response in disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient’s genetic profile. PMID:19506728
Kim, Sollip; Yun, Yeo Min; Chae, Hyo Jin; Cho, Hyun Jung; Ji, Misuk; Kim, In Suk; Wee, Kyung A; Lee, Woochang; Song, Sang Hoon; Woo, Hye In; Lee, Soo Youn; Chun, Sail
Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.
Kim, Sollip; Yun, Yeo-Min; Chae, Hyo-Jin; Cho, Hyun-Jung; Ji, Misuk; Kim, In-Suk; Wee, Kyung-A; Lee, Woochang; Song, Sang Hoon; Woo, Hye In
Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings. PMID:28029011
Kapur, Bhushan M; Lala, Prateek K; Shaw, Julie L V
The experience of chronic pain is one of the commonest reasons individuals seek medical attention, making the management of chronic pain a major issue in clinical practice. Drug metabolism and responses are affected by many factors, with genetic variations offering only a partial explanation of an individual's response. There is a paucity of evidence for the benefits of pharmacogenetic testing in the context of pain management. We reviewed the literature between 2000 and 2013, and references cited therein, using various keywords related to pain management, pharmacology and pharmacogenetics. Opioids continue to be the mainstay of chronic pain management. Several non-opioid based therapies, such as treatment with cannabinoids, gene therapy and epigenetic-based approaches are now available for these patients. Adjuvant therapies with antidepressants, benzodiazepines or anticonvulsants can also be useful in managing pain. Currently, laboratory monitoring of pain management patients, if performed, is largely through urine drug measurements. Drug half-life calculations can be used as functional markers of the cumulative effect of pharmacogenetics and drug-drug interactions. Assessment of half-life and therapeutic effects may be more useful than genetic testing in preventing adverse drug reactions to pain medications, while ensuring effective analgesia. Definitive, mass spectrometry-based methods, capable of measuring parent drug and metabolite levels, are the most useful assays for this purpose. Urine drug measurements do not necessarily correlate with serum drug concentrations or therapeutic effects. Therefore, they are limited in their use in monitoring efficacy and toxicity. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Genomic discoveries in the field of perioperative medicine and anaesthesia have generated multiple publications and some hope that pharmacogenetic testing may guide clinicians to provide safe and effective medicine in a 'tailored' manner. Within the field of anaesthesia, many consider that 'titration of drugs to the desired effect works just fine' and wonder if pharmacogenomics will ever impact on their daily practice. This review will cite practical examples of relevant candidates genes and common polymorphisms that have shown to alter the response to medication prescribed in the peripartum period by obstetricians and anaesthesiologists.
Acosta, Andres; Camilleri, Michael
Irritable bowel syndrome (IBS) is a chronic disease characterized by complex interactions between genetic predisposition and the environment. Current treatments for IBS are characterized by a highly variable response. Gene variations may result from insertions or deletions, gene rearrangements, splice variants or copy number variants, or, more commonly, from substitutions in the DNA of one (single nucleotide polymorphism [SNPs]) or more than one nucleotide. The objective of this editorial is to review the potential importance of pharmacogenetics in the treatment of IBS based on current evidence.
Some goals of this network are as follows: Extend U.S. technological leadership in high performance computing and computer communications; Provide wide dissemination and application of the technologies both to the speed and the pace of innovation and to serve the national economy, national security, education, and the global environment; and Spur gains in the U.S. productivity and industrial competitiveness by making high performance computing and networking technologies an integral part of the design and production process. Strategies for achieving these goals are as follows: Support solutions to important scientific and technical challenges through a vigorous R and D effort; Reduce the uncertainties to industry for R and D and use of this technology through increased cooperation between government, industry, and universities and by the continued use of government and government funded facilities as a prototype user for early commercial HPCC products; and Support underlying research, network, and computational infrastructures on which U.S. high performance computing technology is based.
Möller, H J; Rujescu, D
Pharmacogenetic influences on therapeutic response to e.g. antidepressant or neuroleptic treatment are poorly understood and the lack of efficacy in many of the patients together with side effects can both limit therapy and compliance. Thus the aim of pharmacogenetics and pharmacogenomics is to provide predictive tools for the response to psychopharmacologic agents in the therapy of psychiatric disorders and in that ways to provide a real personalized psychiatry. The following review will summarize the current stage of pharmacogenetics and pharmacogenomics and will critically discuss the possibilities of a personalized medicine.
Haga, Susanne B.
Over the last decade, the number of clinical pharmacogenetic tests has steadily increased as understanding of the role of genes in drug response has grown. However, uptake of these tests has been slow, due in large part to the lack of robust evidence demonstrating clinical utility. We review the evidence behind four pharmacogenetic tests and discuss the barriers and facilitators to uptake: (1) warfarin (drug safety and efficacy); (2) clopidogrel (drug efficacy); (3) codeine (drug safety and efficacy); and (4) abacavir (drug safety). Future efforts should be directed toward addressing these issues and considering additional approaches to generating evidence basis to support clinical use of pharmacogenetic tests. PMID:24020014
Schwartz, Alan; Young, Robin; Hicks, Patricia J.; APPD LEARN, For
Abstract Background: Research networks formalize and institutionalize multi-site collaborations by establishing an infrastructure that enables network members to participate in research, propose new studies, and exploit study data to move the field forward. Although practice-based clinical research networks are now widespread, medical education research networks are rapidly emerging. Aims: In this article, we offer a definition of the medical education practice-based research network, a brief description of networks in existence in July 2014 and their features, and a more detailed case study of the emergence and early growth of one such network, the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN). Methods: We searched for extant networks through peer-reviewed literature and the world-wide web. Results: We identified 15 research networks in medical education founded since 2002 with membership ranging from 8 to 120 programs. Most focus on graduate medical education in primary care or emergency medicine specialties. Conclusions: We offer four recommendations for the further development and spread of medical education research networks: increasing faculty development, obtaining central resources, studying networks themselves, and developing networks of networks. PMID:25319404
Schwartz, Alan; Young, Robin; Hicks, Patricia J
Research networks formalize and institutionalize multi-site collaborations by establishing an infrastructure that enables network members to participate in research, propose new studies, and exploit study data to move the field forward. Although practice-based clinical research networks are now widespread, medical education research networks are rapidly emerging. In this article, we offer a definition of the medical education practice-based research network, a brief description of networks in existence in July 2014 and their features, and a more detailed case study of the emergence and early growth of one such network, the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN). We searched for extant networks through peer-reviewed literature and the world-wide web. We identified 15 research networks in medical education founded since 2002 with membership ranging from 8 to 120 programs. Most focus on graduate medical education in primary care or emergency medicine specialties. We offer four recommendations for the further development and spread of medical education research networks: increasing faculty development, obtaining central resources, studying networks themselves, and developing networks of networks.
Lancia, P; Adam de Beaumais, T; Jacqz-Aigrain, E
Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.The Pharmacogenomics Journal advance online publication, 28 March 2017; doi:10.1038/tpj.2017.1.
Ma, Qiang; Lu, Anthony Y H
Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. For more than 5 decades, studies of pharmacogenetics have provided ample examples of causal relations between genotypes and drug response to account for phenotypic variations of clinical importance in drug therapy. The convergence of pharmacogenetics and human genomics in recent years has dramatically accelerated the discovery of new genetic variations that potentially underlie variability in drug response, giving birth to pharmacogenomics. In addition to the rapid accumulation of knowledge on genome-disease and genome-drug interactions, there arises the hope of individualized medicine. Here we review recent progress in the understanding of genetic contributions to major individual variability in drug therapy with focus on genetic variations of drug target, drug metabolism, drug transport, disease susceptibility, and drug safety. Challenges to future pharmacogenomics and its translation into individualized medicine, drug development, and regulation are discussed. For example, knowledge on genetic determinants of disease pathogenesis and drug action, especially those of complex disease and drug response, is not always available. Relating the many gene variations from genomic sequencing to clinical phenotypes may not be straightforward. It is often very challenging to conduct large scale, prospective studies to establish causal associations between genetic variations and drug response or to evaluate the utility and cost-effectiveness of genomic medicine. Overcoming the obstacles holds promise for achieving the ultimate goal of effective and safe medication to targeted patients with appropriate genotypes.
National Science Foundation, Washington, DC.
A workshop focused on major research issues in networking and communications. This report defines the context for research priorities and initiatives and deals with issues in networking and communications. Fifteen major research priorities and four research specific initiatives were identified by participants as areas that should be pursued over…
Tortelli, Rosanna; Seripa, Davide; Panza, Francesco; Solfrizzi, Vincenzo; Logroscino, Giancarlo
Pharmacogenetics has become extremely important over the last 20 years for identifying individuals more likely to be responsive to pharmacological interventions. The role of genetic background as a predictor of drug response is a young and mostly unexplored field in neurodegenerative diseases. Mendelian mutations in neurodegenerative diseases have been used as models for early diagnosis and intervention. On the other hand, genetic polymorphisms or risk factors for late-onset Alzheimer's disease (AD) or other neurodegenerative diseases, probably influencing drug response, are hardly taken into account in randomized clinical trial (RCT) design. The same is true for genetic variants in cytochrome P450 (CYP), the principal enzymes influencing drug metabolism. A better characterization of individual genetic background may optimize clinical trial design and personal drug response. This chapter describes the state of the art about the impact of genetic factors in RCTs on neurodegenerative disease, with AD, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease as examples. Furthermore, a brief description of the genetic bases of drug response focusing on neurodegenerative diseases will be conducted. The role of pharmacogenetics in RCTs for neurodegenerative diseases is still a young, unexplored, and promising field. Genetic tools allow increased sophistication in patient profiling and treatment optimization. Pharmaceutical companies are aware of the value of collecting genetic data during their RCTs. Pharmacogenetic research is bidirectional with RCTs: efficacy data are correlated with genetic polymorphisms, which in turn define subjects for treatment stratification. © 2016 S. Karger AG, Basel.
Dere, Willard H; Suto, Tamas S
The approval of new medicines has slowed significantly over the past years. In order to accelerate the development of new compounds, novel approaches in drug development are required. Translational medicine or research, an emerging discipline on the frontier of basic science and medical practice, has the potential to enhance the speed and efficiency of the drug development process through the utilization of pharmacogenetics and pharmacogenomics. Pharmacogenetics is the study of genetic causes of individual variations in drug response whereas pharmacogenomics deals with the simultaneous impact of multiple mutations in the genome that may determine the patient's response to drug therapy. The utilization of these methods in the drug development process may therefore identify patient sub-populations that exhibit more effective responses and/or an improved benefit/risk profile upon treatment. The authors provide examples of the use of pharmacogenetics and pharmacogenomics in the fields of cardiovascular, pulmonary, oncological, and bone diseases and also highlight the potential economic value of their development.
Yun, Xiang; Feng, Xiancheng
It is the research hotspot of current broadband network to combine voice service, data service and broadband audio-video service by IP protocol to transport various real time and mutual services to terminal users (home). Home Networking is a new kind of network and application technology which can provide various services. Home networking is called as Digital Home Network. It means that PC, home entertainment equipment, home appliances, Home wirings, security, illumination system were communicated with each other by some composing network technology, constitute a networking internal home, and connect with WAN by home gateway. It is a new network technology and application technology, and can provide many kinds of services inside home or between homes. Currently, home networking can be divided into three kinds: Information equipment, Home appliances, Communication equipment. Equipment inside home networking can exchange information with outer networking by home gateway, this information communication is bidirectional, user can get information and service which provided by public networking by using home networking internal equipment through home gateway connecting public network, meantime, also can get information and resource to control the internal equipment which provided by home networking internal equipment. Based on the general network model of home networking, there are four functional entities inside home networking: HA, HB, HC, and HD. (1) HA (Home Access) - home networking connects function entity; (2) HB (Home Bridge) Home networking bridge connects function entity; (3) HC (Home Client) - Home networking client function entity; (4) HD (Home Device) - decoder function entity. There are many physical ways to implement four function entities. Based on theses four functional entities, there are reference model of physical layer, reference model of link layer, reference model of IP layer and application reference model of high layer. In the future home network
Evers, R; Blanchard, R L; Warner, A W; Cutler, D; Agrawal, N G B; Shaw, P M
Understanding genetic variations that influence pharmacokinetics (PK) in humans is important for optimal clinical use of drugs. Guidances for making decisions on when to conduct pharmacogenetic research during drug development have been proposed by regulatory agencies, but their uniform adoption presents problems due to an inherent lack of flexibility. A questions-based approach (QBA) was developed to enable drug development teams at Merck to iteratively and flexibly evaluate the potential impact of pharmacogenetics (PGx) on clinical pharmacokinetic variability.
Cheok, Meyling H.; Pottier, Nicolas; Kager, Leo
Progress in the treatment of acute leukemia in children has been remarkable, from a disease being lethal four decades ago to current cure rates exceeding 80%. This exemplary progress is largely due to the optimization of existing treatment modalities rather than the discovery of new antileukemic agents. However, despite these high cure rates, the annual number of children whose leukemia relapses after their initial therapy remains greater than that of new cases of most types of childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize treatment and tailor therapy to individual patients, with the goal of optimizing efficacy and safety through better understanding of human genome variability and its influence on drug response. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute lymphoblastic leukemia. These studies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm. PMID:19100367
Griffiths, F; Wild, A; Harvey, J; Fenton, E
Primary care research networks are being publicly funded in the United Kingdom to promote a culture of research and development in primary care. This paper discusses the organisational form of these networks and how their productivity can be evaluated, drawing on evidence from management science. An evaluation of a research network has to take account of the complexity of the organisation, the influence of its local context, and its stage of development. Output measures, such as number of research papers, and process measures, such as number of research meetings, may contribute to an evaluation. However, as networking relies on the development of informal, trust-based relationships, the quality of interactions within a network is of paramount importance for its success. Networks can audit and reflect on their success in promoting such relationships and a more formal qualitative evaluation by an independent observer can document their success to those responsible for funding. PMID:11141879
Nie, Hao; Cai, Xiaoxia; Chen, Hong; Chen, Jian; Weng, Pengfei
In today's world, science and technology make a spurt of progress, so society has entered the era of information technology, network. Only the comprehensive use of electronic warfare and network warfare means can we maximize their access to information and maintain the information superiority. Combined with the specific combat mission and operational requirements, the research design and construction in accordance with the actual military which are Suitable for the future of information technology needs of the tactical Adhoc network, tactical internet, will greatly improve the operational efficiency of the command of the army. Through the study of the network of the U.S. military SINCGARS network, it can explore the routing protocol and mobile model, to provide a reference for the research of our army network.
Holst, Sebastian C; Valomon, Amandine; Landolt, Hans-Peter
Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, γ-amino-butyric acid, and adenosine as important players in the regulation and maintenance of sleep-wake-dependent changes in neuronal activity and the sleep-wake continuum. Dysregulation of these neurochemical systems leads to sleep-wake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. To evaluate opportunities for evidence-based personalized medicine with present and future sleep-wake therapeutics, we review here the impact of known genetic variants affecting exposure of and sensitivity to drugs targeting the neurochemistry of sleep-wake regulation and the pathophysiology of sleep-wake disturbances. Many functional polymorphisms modify drug response phenotypes relevant for sleep. To corroborate the importance of these and newly identified variants for personalized sleep-wake therapy, human sleep pharmacogenetics should be complemented with pharmacogenomic investigations, research about sleep-wake-dependent pharmacological actions, and studies in mice lacking specific genes. These strategies, together with future knowledge about epigenetic mechanisms affecting sleep-wake physiology and treatment outcomes, may lead to potent and safe novel therapies for the increasing number of sleep-disordered patients (e.g., in aged populations).
Shah, Rashmi R; Shah, Devron R
The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as 'the right drug at the right dose the first time.' These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients. © 2012 The Authors
This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs. PMID:20038497
Mei, Lin; Ontiveros, Evelena P.; Griffiths, Elizabeth A.; Thompson, James E.; Wang, Eunice S.; Wetzler, Meir
Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30 years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20–40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including L-asparaginase, glucocorticoids, 6-mercaptopruine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapy. PMID:25614322
Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir
Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.
The Comprehensive Oncologic Emergencies Research Network (CONCERN) was established in March 2015 with the goal to accelerate knowledge generation, synthesis and translation of oncologic emergency medicine research through multi-center collaborations.
The USDA ARS Research Unit based at the Jornada Experimental Range outside of Las Cruces, NM, is a member of the USDA's Long Term Agro-ecosystem Research (LTAR) Network, the National Science Foundation's Long Term Ecological Research (LTER) Network, the National Ecological Observation Network (NEON), and the USDA's Climate Hub Network. Each of these networks has distinct functions, missions, operational characteristics, and distinct scientific and management sub-cultures (though some are fairly new and developing). Some are a fairly independent collection of research sites functioning as a network in name only, and others are truly working to develop a research synergy that could be holistic and uniquely productive. All have real scientific value, and collectively represent an investment in US research infrastructure in biology and agriculture in excess of $3B. To effectively utilize and exploit this unique research infrastructure will require a concerted effort to meld attributes of each to the benefits of their common stakeholders. Real opportunities exist to collectively utilize this infrastructure to address grand research challenges.
The Division of Cancer Prevention supports major scientific collaborations and research networks at more than 100 sites across the United States. Seven Major Programs' sites are shown on this map. | The Division of Cancer Prevention supports major scientific collaborations and research networks at more than 100 sites across the United States.
Pierce, Jean; Cooley, William W.
Discusses application of microcomputer technology to educational research and describes the possible uses of computer networking for communication with colleagues. Focuses on the organization and structure of the Education Research Forum on CompuServe. Considers advantages and costs of networking in general and for the American Educational…
Macleod, Christopher Kit
There is a need to improve the production, sharing and use of collaborative knowledge of catchment systems through networks of researchers, policy makers and practitioners. This requires greater levels of systems based integrative research. In parallel to the growing realization that greater levels of collaborative knowledge in scientific research networks are required, a digital revolution has been taking place. This has been driven primarily by the emergence of distributed networks of computers and standards-based interoperability. The objective of this paper is to present the status and research needs for greater levels of systems based integrative research for the production, sharing and use of collaborative knowledge in catchment research networks. To enable increased levels of integrative research depends on development and application of digital technologies to improve collection, use and sharing of data and devise new knowledge infrastructures. This paper focuses on the requirements for catchment observatories that integrate existing and novel physical, social and digital networks of knowledge infrastructures. To support this focus, I present three leading international examples of collaborative networks of catchment researchers and their development of catchment observatories. In particular, the digital infrastructures they have developed to support collaborative knowledge in catchment research networks. These examples are from North America (NSF funded CUAHSI HIS) and from Europe (UK NERC funded EVOp and the German Helmholtz Association Centers funded TERENO/TEODOOR). These exemplars all supported advancing collaborative knowledge in catchment research networks through the development of catchment observatories. I will conclude by discussing the future research directions required for greater levels of production, sharing and use of collaborative knowledge in catchment research networks based on catchment systems science.
Maupome, Gerardo; McCranie, Ann
The present overview of research methods describes a scientific enquiry paradigm that is well established in other disciplines, including health research, but that is fairly new to oral health research. Social networks analysis (SNA) or network science research is a set of relational methods purporting to identify and characterize the connections between members of a system or network, as well as the structure of the network. Persons and communities making up the members of networks have commonly been the focus of SNA studies but corporations or living organisms might just as well be organized in networks. SNA is grounded in both graphic imagery and computational models. SNA is based on the assumptions that features and structure of networks are amenable to characterization, that such information sheds light on the ways members of the network relate to each other (sharing information, diseases, norms, and so on), and that through these connections between members the overall network structure and characteristics are shaped. The overview resorts to examples specific to oral health themes and proposes a few general avenues for population-based research.
Trent, Ronald J; Cheong, Pak Leng; Chua, Eng Wee; Kennedy, Martin A
Understanding human genetic variation and how it impacts on gene function is a major focus in genomic-based research. Translation of this knowledge into clinical care is exemplified by pharmacogenetics/pharmacogenomics. The identification of particular gene variants that might influence drug uptake, metabolism, distribution or excretion promises a more effective personalised medicine approach in choosing the right drug or its dose for any particular individual. Adverse drug responses can then be avoided or mitigated. An understanding of germline or acquired (somatic) DNA mutations can also be used to identify drugs that are more likely to be therapeutically beneficial. This represents an area of growing interest in the treatment of cancer.
Lopez-Lopez, Elixabet; Gutierrez-Camino, Angela; Bilbao-Aldaiturriaga, Nerea; Pombar-Gomez, Maria; Martin-Guerrero, Idoia; Garcia-Orad, Africa
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients for which therapy fails while some patients experience severe toxicity. In the last few years, several pharmacogenetic studies have been performed to search for markers of outcome and toxicity in pediatric ALL. However, to date, TPMT is the only pharmacogenetic marker in ALL with clinical guidelines for drug dosing. In this article, we will provide an overview of the most important findings carried out in pharmacogenetics for pediatric ALL, such as the interest drawn by methotrexate transporters in the context of methotrexate treatment. Even if most of the studies are centered on coding genes, we will also point to new approaches focusing on noncoding regions and epigenetic variation that could be interesting for consideration in the near future.
Toffoli, Giuseppe; Cecchin, Erika
Although new drugs and association regimens have been used in recent years, the chemotherapeutic outcome for gastric cancer is still poor and improvement in patient survival is not satisfactory. Pharmacogenetics could represent a useful approach to optimize chemotherapeutic treatments in order to identify individuals that are true candidates for clinical benefits from therapy, avoiding the development of severe side effects. The most recent update regarding gastric cancer pharmacogenetics highlights a prominent role of genetic polymorphisms of thymidylate synthase and glutathione S-transferase in the pharmacological treatment with commonly used drugs, such as 5-fluorouracil and platinum derivatives. In order to validate the genetic markers, further larger scale and controlled studies are required. A future challenge is represented by the introduction of targeted therapy in gastric cancer treatment, with the potential emerging tool of pharmacogenetic impact on this field.
Mirzakhani, Hooman; van Noorden, Martijn S; Swen, Jesse; Nozari, Ala; Guchelaar, Henk-Jan
Electroconvulsive therapy (ECT) has shown apparent efficacy in treatment of patients with depression and other mental illnesses who do not respond to psychotropic medications or need urgent control of their symptoms. Pharmacogenetics contributes to an individual's sensitivity and response to a variety of drugs. Clinical insights into pharmacogenetics of ECT and adjunctive medications not only improves its safety and efficacy in the indicated patients, but can also lead to the identification of novel treatments in psychiatric disorders through understanding of potential molecular and biological mechanisms involved. In this review, we explore the indications of pharmacogenetics role in safety and efficacy of ECT and present the evidence for its role in patients with psychiatric disorders undergoing ECT.
Zineh, Issam; Mummaneni, Padmaja; Lyndly, Jenna; Amur, Shashi; La Grenade, Lois A; Chang, Stephen H; Rogers, Hobart; Pacanowski, Michael A
Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics.
Farrell, Martilias S.; Roth, Bryan L.
Pharmacology, in its broadest interpretation, is defined as the study of the interaction between physiological entities and drugs. In modern neuropsychopharmacology, this interaction is viewed as the drug itself on one side and signal transducer (receptor), the signal transduction cascade (effector proteins, second messengers), the cellular response (transcriptional regulation, activity modulation), the organ response (brain circuitry modulation), and, finally, the whole organism response (behavior) on the other. In other words, pharmacology has structured itself around the idea that the exogenous molecule (the drug) encodes a “signal” leading to everything on the other side including, in extreme renditions, a physiological response. The inference is that engaging a particular signal transduction pathway in a defined cell type leads inexorably to a prototypic physiological response. Thus, for instance, serotonergic activation of 5-HT2A receptors in rat aortic smooth muscle cells leads to an increase in intracellular Ca++ (via IP3 release) and smooth muscle contraction (Roth et al., 1986). Here, we suggest that the invention of synthetic ligand – GPCR pairs (aka DREADDs, RASSLS, ‘pharmacogenetics’) permits the study of pharmacology using a shifted equation: more of the signal transduction elements moved to the left and, subsequently, under experimental control. For the purposes of disambiguation and to clarify this new interpretation as a creation of pharmacological manipulation, we present the term pharmacosynthetics to describe what has heretofore been called pharmacogenetics or chemicogenetics. This review discusses this new interpretation and reviews recent applications of the technology and considerations of the approach. PMID:23063887
He, Wei; Li, Zhixiong; Xie, Guotao
With the rapid development of the world economy, road transport has become increasingly busy. An unexpected incident would cause serious traffic disaster due to traffic accidents. To solve this problem, the intelligent transportation system (ITS), which is important for the health developments of the city transportation, has become a hot topic. The car networking provides a new way for intelligent transportation system. It can ensure intelligent control and monitoring of urban road with high performance. This paper described the concept of car networking and related technology both in oversea and domestic. The importance of car networking to achieve vehicle and details of the car networking related technologies were illustrated firstly. Then, attentions focus on the research nodus of the car networking. Lastly, the development trend of car networking research was discussed.
Melodia, Tommaso; Akyildiz, Ian F.
This chapter discusses the state of the art and the major research challenges in architectures, algorithms, and protocols, for wireless multimedia sensor networks (WMSNs). These are networks of wirelessly interconnected smart devices designed and deployed to retrieve video and audio streams, still images, and scalar sensor data. First, applications and key factors influencing the design of WMSNs are discussed. Then, the existing solutions at the application, transport, network, link, and physical layers of the communication protocol stack are investigated. Finally, fundamental open research issues are discussed and future research trends in this area are outlined.
Rancic, Nemanja; Dragojevic-Simic, Viktorija; Vavic, Neven; Kovacevic, Aleksandra; Segrt, Zoran; Djordjevic, Natasa
Renal transplantation is the treatment of choice for the patients with end-stage renal failure. Genetic factors, among others, can influence variability in response to immunosuppressive drugs. Nowadays, due to restrictive health resources, the question arises whether routine pharmacogenetic analyses should be done in the renal transplant recipients or not. The aim of this literature review was to present the up-to-date information considering the economic feasibility of pharmacogenetic testing in patients subjected to renal transplantation. The organization United Network for Organ Sharing in the US estimated that total costs per renal transplant concerning these analyses were $334,300 in 2014. Pharmacogenetic testing prior to treatment initiation could be helpful to predict and assess treatment response and the risks for adverse drug reactions. This kind of testing before treatment initiation seems to be one of the most promising applications of pharmacokinetics. Although pharmacogenetic tests were found to be a cost-effective or cost-saving strategy in many cases, some authors represent another opinion. However, if the real costs of renal transplantation are recognized, the application of these tests in the standard daily practice could be considered more realistic, which additionally emphasizes the importance of future studies assessing their cost effectiveness. PMID:27630984
β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients. PMID:18437562
Kafle, A.; Mukhopadhyay, P.; Nepal, M.; Shyamsundar, P.
In South Asia, a majority of institutions are ill-equipped to undertake research on multi-disciplinary environmental problems, though these problems are increasing at a fast rate and connected to the region's poverty and growth objectives. In this context, the South Asian Network for Development and Environmental Economics (SANDEE) tries to fill a research, training and knowledge gap by building skills in the area of Environment and Development Economics. In this paper, the authors argue that research networks contribute to the growth of sustainability knowledge through (a) knowledge creation, (b) knowledge transfer and (c) knowledge deepening. The paper tries to show the relationship between capacity building, mentorship and research scholarship. It demonstrates that researchers, by associating with the network and its multiple training and mentoring processes, are able to build skills, change curricula and deliver useful knowledge products. The paper discusses the need for interdisciplinary research and the challenges of bridging the gap between research outputs and policy reforms.
Shuldiner, Alan R.; Palmer, Kathleen; Pakyz, Ruth E.; Alestock, Tameka D.; Maloney, Kristin A.; O’Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B.; Pollin, Toni I.; Kelemen, Mark D.; Beitelshees, Amber L.; Robinson, Shawn W.; Blitzer, Miriam G.; McArdle, Patrick F.; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y.; Ambulos, Nicholas; Vesely, Mark R.
Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within five hours along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. PMID:24616408
Johnson, JA; Gong, L; Whirl-Carrillo, M; Gage, BF; Scott, SA; Stein, CM; Anderson, JL; Kimmel, SE; Lee, MTM; Pirmohamed, M; Wadelius, M; Klein, TE; Altman, RB
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 geno-type data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.1 PMID:21900891
Gunter, Helen M.
Legislation requiring site-based performance management in British schools gave rise to the development of practitioner research networks, in which instrumental performance appraisal has predominated over humanist and critical approaches. Even marginalized networks have involved important collaborations among teachers, higher education…
Cooperative agreement (U54) awards to establish Specialized Research Resource Centers that will participate as members of a network of inter-disciplinary, inter-institutional research teams for the purpose of supporting translational research in optical imaging and/or spectroscopy in vivo, with an emphasis on multiple modalities.
VELA NETWORK EVALUATION AND AUTOMATIC PROCESSING RESEARCH William H. Swindell Texas Instruments, Incorporated Prepared for: Air Force Technical...Incorporated Equipment Group Dallas, Texas 75222 CONTROLLING OFFICE NAME AND ADDRESS Advanced Research Projects Agency Nuclear Monitor mg... RESEARCH 1. D D TEXAS INSTRUMENTS INCORPORATED Equipment Group Post Office Box 6015 Dallas, Texas 75222 Prepared for AIR FORCE TECHNICAL
Ringsberg, Karin C
The Nordic Health Promotion Research Network (NHPRN) was established in 2007 at the Nordic School of Public Health (NHV). This article aims to describe the foundation of the NHPRN, the development and the present status of the work of NHPRN. The NHPRN consists of about 50 senior and junior researchers from all Nordic countries. It is a working network that aims to develop the theoretical understanding of health promotion, to create research cooperation in health promotion from a Nordic perspective and to extend the scope of health promotion through education. Network members meet biannually to discuss and further develop research within the field and are also responsible for the Nordic conference on Health Promotion, organized every 3 years. The NHV hosted the network between 2007 and 2014; and the World Health Organisation (WHO) will assume this role in 2015. © 2015 the Nordic Societies of Public Health.
Kozma, Robert; Bressler, Steven; Perlovsky, Leonid; Venayagamoorthy, Ganesh Kumar
The present Special Issue "Advances in Neural Networks Research: IJCNN2009" provides a state-of-art overview of the field of neural networks. It includes 39 papers from selected areas of the 2009 International Joint Conference on Neural Networks (IJCNN2009). IJCNN2009 took place on June 14-19, 2009 in Atlanta, Georgia, USA, and it represents an exemplary collaboration between the International Neural Networks Society and the IEEE Computational Intelligence Society. Topics in this issue include neuroscience and cognitive science, computational intelligence and machine learning, hybrid techniques, nonlinear dynamics and chaos, various soft computing technologies, intelligent signal processing and pattern recognition, bioinformatics and biomedicine, and engineering applications.
aspects. Kleinrock  comments on this result, for example. In 1976, Burke  provided the first proof of some of what was occurring in the flow...server first passes through other servers (as for example in Jackson networks with loops) that item is delayed on its return. All current knowledge about...system simplification. A simplification is an operation on the system such that a new system is obtained subject to two requirements. First , the
Wagholikar, Kavishwar B.; Jain, Rahul; Oliveira, Eliel; Mandel, Joshua; Klann, Jeffery; Colas, Ricardo; Patil, Prasad; Yadav, Kuladip; Mandl, Kenneth D.; Carton, Thomas; Murphy, Shawn N.
Research networks for data sharing are growing into a large platform for pragmatic clinical trials to generate quality evidence for shared medical decision-making. Institutions partnering in the networks have made large investments in developing the infrastructure for sharing data. We investigate whether institutions partnering on Patient-Centered Outcomes Research Institute’s (PCORI) network can share clinical apps. At two different sites, we imported patient data in PCORI’s clinical data model (CDM) format into i2b2 repositories, and adapted the SMART-on-FHIR cell to perform CDM-to-FHIR translation, serving demographics, laboratory results and diagnoses. We performed manual validations and tested the platform using four apps from the SMART app gallery. Our study demonstrates an approach to extend the research infrastructure to allow the partnering institutions to run shared clinical apps, and highlights the involved challenges. Our results, tooling and publically accessible data service can potentially transform research networks into clinical app sharing networks and pave the way towards a learning health system. PMID:28815145
Wagholikar, Kavishwar B; Jain, Rahul; Oliveira, Eliel; Mandel, Joshua; Klann, Jeffery; Colas, Ricardo; Patil, Prasad; Yadav, Kuladip; Mandl, Kenneth D; Carton, Thomas; Murphy, Shawn N
Research networks for data sharing are growing into a large platform for pragmatic clinical trials to generate quality evidence for shared medical decision-making. Institutions partnering in the networks have made large investments in developing the infrastructure for sharing data. We investigate whether institutions partnering on Patient-Centered Outcomes Research Institute's (PCORI) network can share clinical apps. At two different sites, we imported patient data in PCORI's clinical data model (CDM) format into i2b2 repositories, and adapted the SMART-on-FHIR cell to perform CDM-to-FHIR translation, serving demographics, laboratory results and diagnoses. We performed manual validations and tested the platform using four apps from the SMART app gallery. Our study demonstrates an approach to extend the research infrastructure to allow the partnering institutions to run shared clinical apps, and highlights the involved challenges. Our results, tooling and publically accessible data service can potentially transform research networks into clinical app sharing networks and pave the way towards a learning health system.
DiStefano, Johanna K.; Watanabe, Richard M.
A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D. PMID:20936101
Distefano, Johanna K; Watanabe, Richard M
A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of 'response' can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for "individualized medicine" for patients with T2D.
Mas, Sergi; Gassó, Patricia; Lafuente, Amelia
Pharmacogenetics has been driven by a candidate gene approach. The disadvantage of this approach is that is limited by our current understanding of the mechanisms by which drugs act. Gene expression could help to elucidate the molecular signatures of antipsychotic treatments searching for dysregulated molecular pathways and the relationships between gene products, especially protein-protein interactions. To embrace the complexity of drug response, machine learning methods could help to identify gene-gene interactions and develop pharmacogenetic predictors of drug response. The present review summarizes the applicability of the topics presented here (gene expression, network analysis and gene-gene interactions) in pharmacogenetics. In order to achieve this, we present an example of identifying genetic predictors of extrapyramidal symptoms induced by antipsychotic.
Osterkamp, W.R.; Gray, J.R.
An “International Watershed Research Network” is to be an initial project of the Sino-U. S. Centers for Soil and Water Conservation and Environmental Protection. The Network will provide a fundamental database for research personnel of the Centers, as well as of the global research community, and is viewed as an important resource for their successful operation. Efforts are under way to (a) identify and select candidate watersheds, (b) develop standards and protocols for data collection and dissemination, and (c) specify other data sources on erosion, sediment transport, hydrology, and ancillary information of probable interest and use to participants of the Centers. The initial focus of the Network will be on water-deficient areas. Candidate watersheds for the Network are yet to be determined although likely selections include the Ansai Research Station, northern China, and the Walnut Gulch Experimental Watershed, Arizona, USA. The Network is to be patterned after the Vigil Network, an open-ended group of global sites and small drainage basins for which Internet-accessible geomorphic, hydrologic, and biological data are periodically collected or updated. Some types of data, using similar instruments and observation methods, will be collected at all watersheds selected for the Network. Other data from the watersheds that may reflect individual watershed characteristics and research objectives will be collected as well.
This abstract proposes a discussion of how professional science communication and scientific cooperation can become more efficient through the use of modern social network technology, using the example of Mendeley. Mendeley is a research workflow and collaboration tool which crowdsources real-time research trend information and semantic annotations of research papers in a central data store, thereby creating a "social research network" that is emergent from the research data added to the platform. We describe how Mendeley's model can overcome barriers for collaboration by turning research papers into social objects, making academic data publicly available via an open API, and promoting more efficient collaboration. Central to the success of Mendeley has been the creation of a tool that works for the researcher without the requirement of being part of an explicit social network. Mendeley automatically extracts metadata from research papers, and allows a researcher to annotate, tag and organize their research collection. The tool integrates with the paper writing workflow and provides advanced collaboration options, thus significantly improving researchers' productivity. By anonymously aggregating usage data, Mendeley enables the emergence of social metrics and real-time usage stats on top of the articles' abstract metadata. In this way a social network of collaborators, and people genuinely interested in content, emerges. By building this research network around the article as the social object, a social layer of direct relevance to academia emerges. As science, particularly Earth sciences with their large shared resources, become more and more global, the management and coordination of research is more and more dependent on technology to support these distributed collaborations.
Balaji, V.; Boden, Tom; Cowley, Dave; Dart, Eli; Dattoria, Vince; Desai, Narayan; Egan, Rob; Foster, Ian; Goldstone, Robin; Gregurick, Susan; Houghton, John; Izaurralde, Cesar; Johnston, Bill; Joseph, Renu; Kleese-van Dam, Kerstin; Lipton, Mary; Monga, Inder; Pritchard, Matt; Rotman, Lauren; Strand, Gary; Stuart, Cory; Tatusova, Tatiana; Tierney, Brian; Thomas, Brian; Williams, Dean N.; Zurawski, Jason
The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet be a highly successful enabler of scientific discovery for over 25 years. In November 2012, ESnet and the Office of Biological and Environmental Research (BER) of the DOE SC organized a review to characterize the networking requirements of the programs funded by the BER program office. Several key findings resulted from the review. Among them: 1) The scale of data sets available to science collaborations continues to increase exponentially. This has broad impact, both on the network and on the computational and storage systems connected to the network. 2) Many science collaborations require assistance to cope with the systems and network engineering challenges inherent in managing the rapid growth in data scale. 3) Several science domains operate distributed facilities that rely on high-performance networking for success. Key examples illustrated in this report include the Earth System Grid Federation (ESGF) and the Systems Biology Knowledgebase (KBase). This report expands on these points, and addresses others as well. The report contains a findings section as well as the text of the case studies discussed at the review.
Roscam Abbing, Henriette D C
Developments in pharmacogenetics make it possible to determine the genetic factors that influence variations in response to medicine. Differences in response to medication may be related to the genetic characteristics of the individual, to the genetic make-up of the diseased tissue or to both. Advantages include optimal therapeutic effect, safe medication, minimised side-effects, and development of medication for small groups of patients. Strict adherence to patients' rights and to the medical professional standard must prevent negative effects of pharmacogenetics on individual rights, notably the right (not) to know, to privacy and informed consent. Use of pharmacogenetics by third parties for non-health related purposes may bring about a disproportionate intrusion of the privacy of an individual; it may result in barriers for accessing primary social goods, and it may be a disincentive for the individual to have a pharmacogenetic analysis performed for individual health care purposes or to participate in a drug trial. Medical examinations before employment must be justified by the health requirements unavoidably inherent to the job (their objective being the protection of health and not the financial interests of the employer). In a system that relies on private insurance for having access to primary social goods (health, disability--and life insurance), the use and the outcome of a pharmacogenetic analysis for the purpose of differentiation between insurance candidates on the basis of their "risk-profile" must be restricted; where appropriate measures should take into account justified interests of the insurance company to prevent adverse selection. Current measures in several European countries are not effective enough to meet the concerns specifically inherent to pahrmacogenetics. Human rights principles must be at the basis of national and European policies for providing adequate protection against disproportionate intrusion into private life, for
Richter, Trevor A.
Clinical research has become increasingly globalized, but the extent of globalization has not been assessed. To describe the globalization of clinical research, we used all (n = 13,208) multinational trials registered at ClinicalTrials.gov to analyzed geographic connections among individual countries. Our findings indicate that 95% (n = 185) of all countries worldwide have participated in multinational clinical research. Growth in the globalization of clinical research peaked in 2009, suggesting that the global infrastructure that supports clinical research might have reached its maximum capacity. Growth in the globalization of clinical research is attributable to increased involvement of non-traditional markets, particularly in South America and Asia. Nevertheless, Europe is the most highly interconnected geographic region (60.64% of global connections), and collectively, Europe, North America, and Asia comprise more than 85% of all global connections. Therefore, while the expansion of clinical trials into non-traditional markets has increased over the last 20 years and connects countries across the globe, traditional markets still dominate multinational clinical research, which appears to have reached a maximum global capacity. PMID:25517976
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Vandel, P; Talon, J M; Haffen, E; Sechter, D
The importance of pharmacogenetics in medicine is growing with the identification of genetic variability by faster screening methods using automatic sequencers. A particularly interesting finding is that apart from environmental and psychological factors, drug response may be influenced by several biological factors as a result of genetic determinants leading to interindividual variability. Several mutations in genes coding for enzymes of the drug metabolizing system, as well as for neurotransmitter receptors or degrading enzymes and monoamine transport proteins, have been identified and investigated in psychiatry. But, despite the fact that some genetic polymorphisms of enzymes (mainly cytochrome P450 2D6) are well known, the application of pharmacogenetics as a therapeutic tool for improving patient care is rare. This review has three parts. In the first an overview is given of CYP450 characteristics and the genetic polymorphisms of interest to psychiatry. In the second the clinical implications of the CYP2D6 polymorphism are reviewed and in the third part other aspects on pharmacogenetic research in psychiatry are discussed. The aim of our review is to promote the application of pharmacogenetics in everyday clinical practice.
Schlager, Mark S.; Farooq, Umer; Fusco, Judith; Schank, Patricia; Dwyer, Nathan
The authors argue that conceptual and methodological limitations in existing research approaches severely hamper theory building and empirical exploration of teacher learning and collaboration through cyber-enabled networks. They conclude that new frameworks, tools, and techniques are needed to understand and maximize the benefits of teacher…
Schlager, Mark S.; Farooq, Umer; Fusco, Judith; Schank, Patricia; Dwyer, Nathan
The authors argue that conceptual and methodological limitations in existing research approaches severely hamper theory building and empirical exploration of teacher learning and collaboration through cyber-enabled networks. They conclude that new frameworks, tools, and techniques are needed to understand and maximize the benefits of teacher…
Clancy, Carolyn M; Margolis, Peter A; Miller, Marlene
Moving significant therapeutic discoveries beyond early biomedical translation or T1 science and into practice involves: (1) T2 science, identifying "the right treatment for the right patient in the right way at the right time" (eg, patient-centered outcomes research) and tools to implement this knowledge (eg, guidelines, registries); and (2) T3 studies addressing how to achieve health care delivery change. Collaborative improvement networks can serve as large-scale, health system laboratories to engage clinicians, researchers, patients, and parents in testing approaches to translate research into practice. Improvement networks are of particular importance for pediatric T2 and T3 research, as evidence to establish safety and efficacy of therapeutic interventions in children is often lacking. Networks for improvement and research are also consistent with the Institute of Medicine's Learning Healthcare Systems model in which learning networks provide a system for improving care and outcomes and generate new knowledge in near real-time. Creation of total population registries in collaborative network sites provides large, representative study samples with high-quality data that can be used to generate evidence and to inform clinical decision-making. Networks use collaboration, data, and quality-improvement methods to standardize practice. Therefore, variation in outcomes due to unreliable and unnecessary care delivery is reduced, increasing statistical power, and allowing a consistent baseline from which to test new strategies. In addition, collaborative networks for improvement and research offer the opportunity to not only make improvements but also to study improvements to determine which interventions and combination of strategies work best in what settings.
Steiner, John F.; Paolino, Andrea R.; Thompson, Ella E.; Larson, Eric B.
Purpose: As multi-institutional research networks assume a central role in clinical research, they must address the challenge of sustainability. Despite its importance, the concept of network sustainability has received little attention in the literature, and the sustainability strategies of durable scientific networks have not been described. Innovation: The Health Maintenance Organization Research Network (HMORN) is a consortium of 18 research departments in integrated health care delivery systems with over 15 million members in the United States and Israel. The HMORN has coordinated federally funded scientific networks and studies since 1994. This case study describes the HMORN approach to sustainability, proposes an operational definition of network sustainability, and identifies 10 essential elements that can enhance sustainability. Credibility: The sustainability framework proposed here is drawn from prior publications on organizational issues by HMORN investigators and from the experience of recent HMORN leaders and senior staff. Conclusion and Discussion: Network sustainability can be defined as (1) the development and enhancement of shared research assets to facilitate a sequence of research studies in a specific content area or multiple areas, and (2) a community of researchers and other stakeholders who reuse and develop those assets. Essential elements needed to develop the shared assets of a network include: network governance; trustworthy data and processes for sharing data; shared knowledge about research tools; administrative efficiency; physical infrastructure; and infrastructure funding. The community of researchers within a network is enhanced by: a clearly defined mission, vision and values; protection of human subjects; a culture of collaboration; and strong relationships with host organizations. While the importance of these elements varies based on the membership and goals of a network, this framework for sustainability can enhance strategic
The European Paediatric Regulation (EUPR) calls for the fostering of high quality ethical research and medicinal products to be used in children. The EUPR provides the background, goals, and requirements for paediatric clinical trials. Paediatric clinical trials in children are mandatory to generate data on new drugs as well as on drugs used off-label or for unlicensed indications. The Family Paediatricians Medicines for Children Research Network (FIMP-MCRN) was established in 2003 with the aim of developing competence, infrastructure, networking and education for paediatric clinical trials. The network, consisting of twenty Paediatric Regional Networks has progressed very well and has achieved valuable improvements concerning the conduct of paediatric clinical trials. Furthermore, ad hoc training programs have incremented knowledge about clinical trials in Family Paediatrician Investigators (FPI) and have made medical professionals as well as the public aware of the need and advantages of trials in children. PMID:20591168
Foster, M W; Sharp, R R; Mulvihill, J J
Social categories such as race and ethnicity have long been used in interpreting patient symptoms, diagnosing disease, and predicting therapeutic response. DNA-based diagnostic tests and pharmacogenetic screens could make these uses of social categories largely irrelevant by allowing clinicians to base diagnosis and treatment decisions on the unique genetic features of individual patients. Despite this attractive vision of individualized care, however, social categories are likely to continue playing a significant role in the coming era of genetic medicine. Current uses of social categories in pharmacogenetic research, for example, illustrate how drug development and marketing will perpetuate the use of social categories such as race and ethnicity. Those uses may unintentionally blunt the precision of genetic technologies and pose new threats to socially identifiable populations. These implications suggest the need for greater caution in using social categories as indicators for specific tests or therapies and for federal legislation to protect against discriminatory uses of individuals' genetic information. In addition, more precise social classifications than those presently in use may allow us to realize the full potential of DNA-based technologies, thus minimizing social disparities in health care. Those more precise social classifications should reflect extended patient pedigrees and not the self-reported claims of racial and/or ethnic affiliation.
Jones, Jermaine D; Comer, Sandra D
Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Jones, Jermaine D.; Comer, Sandra D.
Background Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. Methods This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. Results Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. Conclusions Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. PMID:25819021
Johnson, Julie A; Cavallari, Larisa H
The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics.
Aceti, Antonio; Gianserra, Laura; Lambiase, Lara; Pennica, Alfredo; Teti, Elisabetta
Highly active antiretroviral therapy (HAART) has substantially changed human immunodeficiency virus (HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment (tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV (PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a research area with great growth potential which may be useful to guide the rational use of antiretrovirals.
Aceti, Antonio; Gianserra, Laura; Lambiase, Lara; Pennica, Alfredo; Teti, Elisabetta
Highly active antiretroviral therapy (HAART) has substantially changed human immunodeficiency virus (HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment (tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV (PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a research area with great growth potential which may be useful to guide the rational use of antiretrovirals. PMID:26279982
Cavallari, Larisa H.
The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics. PMID:23686351
In 2001 Germany's Federal Ministry of Education and Research (BMFM) initiated the National Genome Research Network (NGFN). The goals of the NGFN are the investigation of the molecular basis of common diseases to improve new methods for prevention, diagnosis and therapy. The disease-oriented genome networks investigate cardiovascular diseases, cancer, diseases of the nervous system, diseases due to environmental factors and infection, and inflammation. They are supported by technological platforms and a component for technology transfer. The explicit aims include better integration of public health research and economy in order to gain an efficient economical and technological utilisation and application in community health. This article describes the creation of the NGFN in the context of international and national genome research, shows the structure and content of the NGFN and gives examples for NGFN research in networks on a highly, internationally recognised level.
Lee, Sunhee; Nam, Seungjoo; Jung, Paul E; Kim, Ki-Jeong; Lee, Yeonhee
With the enactment of the Nagoya Protocol, biological resources are now increasingly considered as assets of an individual country, instead of as the common property of mankind. As worldwide interest for securing biological resources intensifies, research resource centers (RRCs), which collect, preserve, and provide resources and their information to academia and industries, are gathering more attention. The Asian Network of Research Resource Centers (ANRRC) strives for conservation and effective use of bioresources and their data by connecting resource centers of Asia, a continent with the greatest diversity of life. Since its foundation in 2009, the Network has significantly expanded to encompass 103 RRCs of 14 countries. Through the Network, member countries discuss opportunities for resource exchange and research collaboration and share biobanking information and regulations of different countries for international harmonization of resource management. ANRRC also contributes to developing of International Standards of biobanks and biological resources as a liaison to the International Organization for Standardization technical committee 276 Biotechnology.
Walden, Lucas M; Brandl, Eva J; Changasi, Amtul; Sturgess, Jessica E; Soibel, Alexander; Notario, Janna Fe D; Cheema, Sheraz; Braganza, Nicole; Marshe, Victoria S; Freeman, Natalie; Tiwari, Arun K; Kennedy, James L; Müller, Daniel J
Pharmacogenetics seeks to improve patient drug response and decrease side effects by personalizing prescriptions using genetic information. Since 2012, by one estimate, the number of patients who have had pharmacogenetic testing has doubled and this number is expected to double again by 2015. Given the increasing evidence for genetic influences on treatment response, we deemed it important to study physicians' opinions of pharmacogenetic testing. Surveys were completed by 168 Canadian physicians who had ordered at least one pharmacogenetic test (in particular for CYP2D6 or CYP2C19) for the prescription of psychiatric medication. Our results indicated that 80% of respondents believe genetic testing would become common standard in psychiatric drug treatment and 76% of respondents reported satisfactory or higher than satisfactory understanding of the pharmacogenetic report provided. Significantly more male physicians believed they had a higher understanding of the pharmacogenetic report compared to female physicians. To our knowledge, this is the only study that has assessed physicians' opinions of pharmacogenetic testing for psychotropic medication after they had received a pharmacogenetic report. Our results demonstrate a positive opinion of physicians on pharmacogenetics and indicate great potential for future clinical application.
Duggan, Anne; Minkovitz, Cynthia S; Chaffin, Mark; Korfmacher, Jon; Brooks-Gunn, Jeanne; Crowne, Sarah; Filene, Jill; Gonsalves, Kay; Landsverk, John; Harwood, Robin
Home visiting can play a key role in the early childhood system of services. For home visiting to achieve its potential, decision-makers must make informed choices regarding adoption, adaptation, coordination, scale-up, and sustainment. We need a coordinated, focused, and theory-based home visiting research infrastructure to inform such decisions. The transdisciplinary Home Visiting Research Network (HVRN) was established in July 2012 with funding from the Health Resources and Services Administration. Its goal is to promote the translation of research findings into policy and practice. Its objectives are to (1) develop a national home visiting research agenda, (2) advance the use of innovative research methods; and (3) provide a research environment that is supportive of the professional development of emerging researchers interested in home visiting. A Management Team designs and directs activities to achieve these objectives through Work Teams. A Steering Committee of national leaders representing stakeholder groups oversees progress. HVRN's Coordinating Center supports the Work Teams and HVRN's Home visiting Applied Research Collaborative, a practice-based research network of home visiting programs. This article describes HVRN's rationale, approach, and anticipated products. We use home visiting-primary care coordination as an illustration, noting potential roles for pediatric practices and pediatric researchers and research educators in HVRN activities. HVRN creates the infrastructure for a rigorous program of research to inform policy and practice on home visiting as part of the system of services to improve family functioning, parenting, and child outcomes.
Sorich, Michael J; Wiese, Michael D; O'Shea, Rebekah L; Pekarsky, Brita
Hypercholesterolaemia is a highly prevalent condition that has major health and cost implications for society. Pharmacotherapy is an important and effective treatment modality for hypercholesterolaemia, with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ('statins') the most commonly used class of drugs. Over the past decade, there has been intensive research to identify pharmacogenetic markers to guide treatment of hypercholesterolaemia. This study aimed to review the evidence of incremental cost, effect and cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia. Three cost-effectiveness analyses (CEAs) were identified that studied the value of screening for genotypes of angiotensin I converting enzyme (ACE), cholesteryl ester transfer protein (CETP), and kinesin family member 6 (KIF6) prior to initiating statin therapy. For all three CEAs, a major limitation identified was the reproducibility of the evidence supporting the clinical effect of screening for the pharmacogenetic marker. Associated issues included the uncertain value of pharmacogenetic markers over or in addition to existing approaches for monitoring lipid levels, and the lack of evidence to assess the effectiveness of alternative therapeutic options for individuals identified as poor responders to statin therapy. Finally, the economic context of the market for diagnostic tests (is it competitive or is there market power?) and the practicality of large-scale screening programmes to inform prescribing in a complex and varied market may limit the generalizability of the results of the specific CEAs to policy outcomes. The genotype of solute carrier organic anion transporter family member 1B1 (SLCO1B1) has recently been associated with increased risk of muscle toxicity with statin therapy and the review identified that exploration of cost effectiveness of this pharmacogenetic marker is likely warranted.
Bauer, M; Banaschewski, T; Heinz, A; Kamp-Becker, I; Meyer-Lindenberg, A; Padberg, F; Rapp, M A; Rupprecht, R; Schneider, F; Schulze, T G; Wittchen, H-U
Mental disorders are among the greatest medical and social challenges facing us. They can occur at all stages of life and are among the most important commonly occurring diseases. In Germany 28 % of the population suffer from a mental disorder every year, while the lifetime risk of suffering from a mental disorder is almost 50 %. Mental disorders cause great suffering for those affected and their social network. Quantitatively speaking, they can be considered to be among those diseases creating the greatest burden for society due to reduced productivity, absence from work and premature retirement. The Federal Ministry of Education and Research is funding a new research network from 2015 to 2019 with up to 35 million euros to investigate mental disorders in order to devise and develop better therapeutic measures and strategies for this population by means of basic and translational clinical research. This is the result of a competitive call for research proposals entitled research network for mental diseases. It is a nationwide network of nine consortia with up to ten psychiatric and clinical psychology partner institutions from largely university-based research facilities for adults and/or children and adolescents. Furthermore, three cross-consortia platform projects will seek to identify shared causes of diseases and new diagnostic modalities for anxiety disorders, attention deficit hyperactivity disorders (ADHS), autism, bipolar disorders, depression, schizophrenia and psychotic disorders as well as substance-related and addictive disorders. The spectrum of therapeutic approaches to be examined ranges from innovative pharmacological and psychotherapeutic treatment to novel brain stimulation procedures. In light of the enormous burden such diseases represent for society as a whole, a sustainable improvement in the financial support for those researching mental disorders seems essential. This network aims to become a nucleus for long overdue and sustained
Stausberg, J.; Altmann, U.; Antony, G.; Drepper, J.; Sax, U.; Schütt, A.
Background Several disease specific registers are operated by members of the ‘TMF – Technology, Methods, and Infrastructure for Networked Medical Research’, an umbrella organization of research networks in Germany. Objective To describe the coverage and the current state as well as financial and organizational issues of registers operated by member networks of the TMF, to identify their requirements and needs, and to recommend best practice models. Methods A survey with a self-completion questionnaire including all 55 TMF member networks was carried out in winter 2007/2008. Interviews focusing on technological issues were conducted and analyzed in summer 2009 with a convenience sample of 10 registers. Results From 55 TMF member networks, 11 provided information about 14 registers. Six registers address diseases of the circulatory system with more than 150,000 registered patients. The interviews revealed a typical setting of “research registers”. Research registers are an important mean to generate hypotheses for clinical research, to identify eligible patients, and to share data with clinical trials. Concerning technical solutions, we found a remarkable heterogeneity. The analysis of the most efficient registers revealed a structure with five levels as best practice model of register management: executive, operations, IT-management, software, hardware. Conclusion In the last ten years, the TMF member networks established disease specific registers in Germany mainly to support clinical research. The heterogeneity of organizational and technical solutions as well as deficits in register planning motivated the development of respective recommendations. The TMF will continue to assist the registers in quality improvement. PMID:23616850
Close, Sandra L
Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines. © 2011 The Author Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.
Zandi, Peter P; Judy, Jennifer T
Existing psychotropic medications for the treatment of mental illnesses, including antidepressants, mood stabilizers, and antipsychotics, are clinically suboptimal. They are effective in only a subset of patients or produce partial responses, and they are often associated with debilitating side effects that discourage adherence. There is growing enthusiasm in the promise of pharmacogenetics to personalize the use of these treatments to maximize their efficacy and tolerability; however, there is still a long way to go before this promise becomes a reality. This article reviews the progress that has been made in research toward understanding how genetic factors influence psychotropic drug responses and the challenges that lie ahead in translating the research findings into clinical practices that yield tangible benefits for patients with mental illnesses.
García-Dorado, David; Castro-Beiras, Alfonso; Díez, Javier; Gabriel, Rafael; Gimeno-Blanes, Juan R; Ortiz de Landázuri, Manuel; Sánchez, Pedro L; Fernández-Avilés, Francisco
Today, cardiovascular disease is the principal cause of death and hospitalization in Spain, and accounts for an annual healthcare budget of more than 4000 million euros. Consequently, early diagnosis, effective prevention, and the optimum treatment of cardiovascular disease present a significant social and healthcare challenge for the country. In this context, combining all available resources to increase the efficacy and healthcare benefits of scientific research is a priority. This rationale prompted the establishment of the Spanish Cooperative Cardiovascular Disease Research Network, or RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares), 5 years ago. Since its foundation, RECAVA's activities have focused on achieving four objectives: a) to facilitate contacts between basic, clinical and epidemiological researchers; b) to promote the shared use of advanced technological facilities; c) to apply research results to clinical practice, and d) to train a new generation of translational cardiovascular researchers in Spain. At present, RECAVA consists of 41 research groups and seven shared technological facilities. RECAVA's research strategy is based on a scientific design matrix centered on the most important cardiovascular processes. The level of RECAVA's research activity is reflected in the fact that 28 co-authored articles were published in international journals during the first six months of 2007, with each involving contributions from at least two groups in the network. Finally, RECAVA also participates in the work of the Spanish National Center for Cardiovascular Research, or CNIC (Centro Nacional de Investigación Cardiovascular), and some established Biomedical Research Network Centers, or CIBER (Centros de Investigación Biomédica en RED), with the aim of consolidating the development of a dynamic multidisciplinary research framework that is capable of meeting the growing challenge that cardiovascular disease will present
Bondon-Guitton, Emmanuelle; Despas, Fabien; Becquemont, Laurent
Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug.
Liu, Rong; Li, Xi; Zhang, Wei; Zhou, Hong-Hao
Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling. BART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84-8.96 mg/week, mean percentage within 20%: 45.88%-46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly higher mean percentage within 20
Appleby, Yvon; Hillier, Yvonne
This paper discusses the contribution that practice-research networks can make to support critical professional development in the Learning and Skills sector in England. By practice-research networks we mean groups or networks which maintain a connection between research and professional practice. These networks stem from the philosophy of…
Kaminski, Jacek W.; Struzewska, Joanna; Markowicz, Krzysztof
Poland-AOD research network (www.polandaod.pl) was formed in 2011. It is a consortium of Polish institutions that are involved in studies of the atmospheric aerosol impact on the climate system. In 2016 the Poland-AOD network comprised of five stations: Radiative Transfer Laboratory, University of Warsaw (urban station), the research station of the Institute of Oceanology, in Sopot (coastal station), Radiative Transfer Station SolarAOT in Strzyzow (background station in the Carpathian mountains), Meteorology and Climatology Observatory at the Nicolaus Copernicus University in Torun (urban station), and the Research station in Rzecin at Poznan University of Life Sciences (rural station). The primary goal of the network is to carry out measurements of aerosol single scattering properties, radiation budget, simulate radiative transfer and aerosol transport, validate aerosol transport and transformation models such as NAAPS and GEM-AQ, as well as carry out instrument calibration and intercomparison. We will present observations of aerosol properties collected by the network as well as results from the GEM-AQ model simulations for selected episodes of biomass burning and urban aerosol.
SCHLEYER, TITUS; BUTLER, BRIAN S.; SONG, MEI; SPALLEK, HEIKO
Science in general, and biomedical research in particular, is becoming more collaborative. As a result, collaboration with the right individuals, teams, and institutions is increasingly crucial for scientific progress. We propose Research Networking Systems (RNS) as a new type of system designed to help scientists identify and choose collaborators, and suggest a corresponding research agenda. The research agenda covers four areas: foundations, presentation, architecture, and evaluation. Foundations includes project-, institution- and discipline-specific motivational factors; the role of social networks; and impression formation based on information beyond expertise and interests. Presentation addresses representing expertise in a comprehensive and up-to-date manner; the role of controlled vocabularies and folksonomies; the tension between seekers’ need for comprehensive information and potential collaborators’ desire to control how they are seen by others; and the need to support serendipitous discovery of collaborative opportunities. Architecture considers aggregation and synthesis of information from multiple sources, social system interoperability, and integration with the user’s primary work context. Lastly, evaluation focuses on assessment of collaboration decisions, measurement of user-specific costs and benefits, and how the large-scale impact of RNS could be evaluated with longitudinal and naturalistic methods. We hope that this article stimulates the human-computer interaction, computer-supported cooperative work, and related communities to pursue a broad and comprehensive agenda for developing research networking systems. PMID:24376309
Barysheva, V O; Ketova, G G
Drug resistance is a phenomenon that has received serious attention in recent years in everyday medical practice. This may also be described as responsiveness or non-responsiveness to drugs, as patients respond partially to medical treatment or have no response at all . The non-responsiveness to clopidogrel in cardiac patients of different populations is due to genetic variations in the cytochrome P450 (CYP) gene . Carriers of at least one 'poor metabolizer allele' of CYP2C19 (either *2 or *3) have lower levels of the active metabolite of clopidogrel and have reduced platelet inhibition . Furthermore, the significant inter-ethnic variability in the allelic frequencies of CYP2C19*2 has been associated with differential clopidogrel resistance . Such mutations in this variant allele are responsible for the inability of the CYP enzyme to convert clopidogrel into its active metabolite, which may result in the increased risk of death, heart attack or stroke among patients who have undergone percutaneous coronary intervention (PCI) . South Ural is a multinational region, a subject of the Russian Federation, where genetic variations have not been studied fully yet. To examine prevalence of mutant alleles in population of South Ural. We conducted pharmacogenetic testing for specific single nucleotide polymorphisms in 54 patients. The present research was conducted in the alleles CYP2C19*2 and CYP2C19*3. The data were processed using the program SPSS Statistics. The mean age of patients was 58, 4 years (from 26 to 79 years). Among all patients 59.3% were male, 40.7% of female patients.Among the studied patients in allele CYP2C19*2, the "wild" type GG was detected in 75,9% of patients, GA type in 22.2% and AA variant was detected in 1.9% of all patients. Allele CYP2C19*3 is often found among alleles with reduced function and also associated with resistance to clopidogrel. Functional drug response is observed in patients with type GG. All of the studied patients
Patel, Bianca D; Barzman, Drew H
Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha-adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments.
Jean L. Steiner; Timothy Strickland; Peter J.A. Kleinman; Kris Havstad; Thomas B. Moorman; M.Susan Moran; Phil Hellman; Ray B. Bryant; David Huggins; Greg McCarty
While current weather patterns and rapidly accelerated changes in technology often focus attention onÂ short-term trends in agriculture, the fundamental demands on modern agriculture to meet society food, feed, fuel andÂ fiber production while providing the foundation for a healthy environment requires long-term perspective. The Long-Â Term Agroecoystem Research Network...
The purpose of pharmacogenetics is to offer"personalised" treatment, in which a drug is only prescribed to patients in whom it is very likely to be effective, or to withhold a drug from patients at increased risk of adverse effects. Pharmacogenetics requires the use of genetic tests which, as with any other diagnostic test, must be evaluated for their discriminatory power (sensitivity, specificity, etc.). These evaluations are sometimes biased. Pharmacogenetics has been heralded as a means of tailoring cancer therapy. However large clinical trials with demanding clinical endpoints are often disappointing, despite initially encouraging results. Pharmacogenetic information is included in many summaries of product characteristics for non-cancer drugs, mainly in order to reduce the frequency of certain serious adverse effects. In summary, pharmacogenetics theoretically represents a step forward but must be evaluated in rigorous clinical trials, as is the case with all other "therapeutic tools".
Chang, Matthew T; McCarthy, Jeanette J; Shin, Jaekyu
Recent large-scale genetic-based studies have transformed the field of pharmacogenetics to identify, characterize and leverage genetic information to inform patient care. Genetic testing can be used to alter drug selection, optimize drug dosing and prevent unnecessary adverse events. As precision medicine becomes the mainstay in the clinic, it becomes critical for clinicians to utilize pharmacogenetics to guide patient care. One primary challenge is identifying patients where genetic tests that can potentially impact patient care. To address this challenge, our review highlights many practical issues clinicians may encounter: identifying candidate patients and clinical laboratories for pharmacogenetic testing, selecting highly curated resources to help asses test validity, reimbursing costs of pharmacogenetic tests, and interpreting of pharmacogenetic test results.
Hersh, Craig P
Similar to other common chronic diseases, chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder with multiple disease subtypes. Candidate gene studies have found genetic associations for COPD-related phenotypes that may be relevant for pharmacogenetics studies, including lung function decline and COPD exacerbations. However, few COPD pharmacogenetics studies have been completed. Most studies have focused on the role of variants in the β2-adrenergic receptor gene on bronchodilator response, but the findings have been inconclusive. Candidate gene studies highlight the concept that genes for COPD susceptibility may also be relevant in COPD pharmacogenetics. Currently, there are no clinical applications of pharmacogenetics to COPD therapy, but the use of pharmacogenetics to determine initial smoking cessation therapy may be closer to clinical application. PMID:20136362
Anwar, Mohamed Subhan; Iskandar, Muhammad Zaid; Parry, Helen M; Doney, Alex S; Palmer, Colin N; Lang, Chim C
Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.
Seyfried, M. S.; Holbrook, W. S.; Fellows, A.; Kormos, P.; Lohse, K. A.; Marks, D. G.; Flerchinger, G. N.
A major benefit of participation in research networks such as the Long Term Agroecosystem Research (LTAR) network is that multidisciplinary research on a broad range of topics is facilitated. The interaction between the Agricultural Research Service long-term experimental watersheds and LTAR exemplifies this. At the Reynolds Creek Experimental Watershed (RCEW), this is further enhanced by participation in the Critical Zone Observatory (CZO) network. The RCEW has a long history (55 years) of experimentation, modeling and monitoring emphasizing hydrologic processes, which are inevitably related to biogeochemical processes, but rarely linked directly in RCEW research. New research with the Reynolds Creek CZO (RC CZO) emphasizes biogeochemistry. The background research and infrastructure at the RCEW provides an ideal platform for that research. At the same time, RC CZO products are enabling ARS to extend its research activities. We highlight three examples: (i) forcing data sets used to facilitate physical modeling of hydrologic and biogeochemical processes, (ii) linkage of hydrology and geophyscis to extend our understanding of subsurface processes, and (iii) climate/elevation linkages to ecosystem productivity, which are closely related in water limited environments such as the RCEW. The addition of the RCEW to the LTAR is further extended ARS capabilities. For example, the RCEW is now monitoring net carbon balance and productivity at sites along an elevation/climatic gradient. The addition of LTAR research enhances that work by extending the climate gradient and introducing management and land surface change effects. We anticipate that these interactions will grow and that cross-site experiments will be initiated as the results begin to accumulate.
Shuldiner, Alan R; Palmer, Kathleen; Pakyz, Ruth E; Alestock, Tameka D; Maloney, Kristin A; O'Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B; Pollin, Toni I; Kelemen, Mark D; Beitelshees, Amber L; Robinson, Shawn W; Blitzer, Miriam G; McArdle, Patrick F; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y; Ambulos, Nicholas; Vesely, Mark R
Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.
Angeles (California) ucsc University of California at Santa Cruz (California) udel University of Delaware (Delaware) Some of the research...UC Santa Cruz , UCLA Multicast-based Inference of Network-internal Characteristics (MINC) multicast-based estimators of the origins of...Measurements by Laser Techniques," Italian Assn. for Laser Velocimetry, Ancona , Italy, 18-21 June 2002 7 Yima: A Second Generation Continuous Media
Kennedy, Marie R.; Kennedy, David P.; Brancolini, Kristine R.
This article describes for the first time the composition and structure of the personal networks of novice librarian researchers. We used social network analysis to observe if participating in the Institute for Research Design in Librarianship (IRDL) affected the development of the librarians' personal networks and how the networks changed over…
Kennedy, Marie R.; Kennedy, David P.; Brancolini, Kristine R.
This article describes for the first time the composition and structure of the personal networks of novice librarian researchers. We used social network analysis to observe if participating in the Institute for Research Design in Librarianship (IRDL) affected the development of the librarians' personal networks and how the networks changed over…
Kronenberg, Sefi; Frisch, Amos; Rotberg, Beni; Carmel, Miri; Apter, Alan; Weizman, Abraham
Selective serotonin reuptake inhibitors (SSRIs) are now an accepted and widely used first-line treatment for pediatric depression and anxiety. However, the data indicate that SSRI treatment achieves a clinical response in only 55-60% of children, and some may develop drug-induced suicidal behavior. Clinicians have no reliable tools to help them identify in advance those youths who are not likely to respond to an SSRI, or who are likely to develop SSRI-induced suicidality. Pharmacogenetic research attempts to identify genetic markers that are associated with response and side-effect profile. This review covers all the pharmacogenetic studies conducted as yet on pediatric samples and compares them with available data on adult samples. An emphasis is put on serotonergic genes such as the serotonin transporter (5-HTT) and additional genes known to be active in the CNS.
Robert, Jacques; Le Morvan, Valérie; Giovannetti, Elisa; Peters, Godefridus J
There are an increasing number of studies devoted to the identification of associations between anticancer drug efficacy and toxicity and common polymorphisms present in the patients' genome. However, many articles presenting the results of such studies do not bring the simple and necessary background information allowing the evaluation of the relevance of the study, its significance and its potential importance for patients' treatment. This position paper first addresses clinical oncologists with the aim of giving them the basic knowledge on pharmacogenetics and on the potential use of gene polymorphisms as predictive biomarkers in routine and clinical research. A secondary objective is to give molecular biologists some recommendations on how to conceive protocols and how to publish their results when they develop pharmacogenetic studies appended to clinical trials or with autonomous goals. Copyright © 2014 Elsevier Ltd. All rights reserved.
Campbell, Jared M; Bateman, Emma; Peters, Micah Dj; Bowen, Joanne M; Keefe, Dorothy M; Stephenson, Matthew D
Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.
Jud Schefer, R; Paine Kuhn, C; Demuth, D
Pharmacogenetics is the study of genetic determinants of different responses to drug therapy and deals with differences in metabolic pathways and therapeutic effects as well as adverse reactions. A common genetic defect found in veterinary medicine is the MDR1 mutation occurring in Collies and related breeds that leads to an altered P-glycoprotein. Genetic mutations of enzymes (cytochrome P450, thiopurine s-methyltransferase, n-acetyltransferase, UDP-glucuronyltransferase, plasma esterase or sulfotransferase), which are responsible for the metabolism of drugs, are found as well. A decreased functional level of these enzymes can lead to an increased plasma concentration of the drug with a consequent relative overdose.
Zhang, Wei; Roederer, Mary W; Chen, Wang-Qing; Fan, Lan; Zhou, Hong-Hao
The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market.
Tzvetkov, Mladen V.
Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance. PMID:18224312
Saraswathi, T. S.; And Others
This report documents the activities of the Research Network, a coordinated effort of the International Development Research Center (IDRC) and the Human Development and Family Studies (HDFS) Department of Baroda University (India) during the period January 1990 to June 1993. The Research Network aimed to establish a network of consultative…
Jie, Wan; Wen, Wang
The building of military logistics network is an important issue for the construction of new forces. This paper has thrown out a concept model of 6R military logistics network model based on JIT. Then we conceive of axis spoke y logistics centers network, flexible 6R organizational network, lean 6R military information network based grid. And then the strategy and proposal for the construction of the three sub networks of 6Rmilitary logistics network are given.
Sajantila, A; Palo, J U; Ojanperä, I; Davis, C; Budowle, B
Medico-legal autopsy is the primary method in determining the cause and manner of death when the death is suspected to be unnatural. In some of these autopsies, the death remains ambiguous, even after a complete autopsy including histological investigation and toxicological screenings. In cases where there are no morphological abnormalities, medico-legal genetics may offer additional means to provide knowledge of possible genetic mutations, which may have initiated the process or predisposed the individual to stress risk conditions leading to death. One class of ambiguous deaths consists of drug-related deaths where the interpretation of the toxicological results are not clear. In such situations post mortem genotyping and the analysis of metabolite rations may provide an insight to the findings. A few cases demonstrating the potential strength of pharmacogenetics in medico-legal context has been published. However, there is a paramount need for serious scientific studies before the field of post mortem pharmacogenetics can be utilized in routine medico-legal analyses casework and brought routinely into courtroom.
Gamelin, E; Boisdron-Celle, M; Morel, A; Capitain, O
Toxic side-effects of cytotoxic drugs is a stumbling-block of chemotherapy due to the fact that their therapeutic index is narrow. New approaches are necessary to individualize the treatments. Pharmacogenetic analysis is facilitated by easy access to the patient genome via simple blood samples, by the large number of known genes of interest coding for drugs targets or metabolism enzymes and by the fact that their polymorphism (SNP) is often known. Presently more focused on the prevention of toxic side-effects, pharmacogenetics already provides a good deal of confirmed data for clinical applications, such as the detection of dihydropyrimidine dehydrogenase deficiency by sequencing, or UGT1A1 7/7 genotype detection in Gilbert's syndrome for the prevention of 5-FU and irinotecan-induced severe toxicities. It must be emphasized that a SNP which is deleterious for enzyme activity is rarely a contraindication for the drug, provided that some precautions are taken and appropriate therapeutic advice is given by experts.
Weitzel, Kristin W; Elsey, Amanda R; Langaee, Taimour Y; Burkley, Benjamin; Nessl, David R; Obeng, Aniwaa Owusu; Staley, Benjamin J; Dong, Hui-Jia; Allan, Robert W; Liu, J Felix; Cooper-Dehoff, Rhonda M; Anderson, R David; Conlon, Michael; Clare-Salzler, Michael J; Nelson, David R; Johnson, Julie A
Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine. © 2014 Wiley Periodicals, Inc.
Seripa, Davide; Panza, Francesco; Daragjati, Julia; Paroni, Giulia; Pilotto, Alberto
The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.
Kirchheiner, Julia; Seeringer, Angela; Viviani, Roberto
More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients. The individual drug metabolizing capacity is assessed by genotyping drug metabolizing enzymes. The potential implications of information gained from genotyping are dose adjustments according to genotype. However, even when the consequences of genotype on pharmacokinetics are significant and well known, as in the case of many tricyclic antidepressants and several SSRIs, there is still considerable controversy on whether adjustment of dosage driven by genetic information may improve therapeutic efficacy, and/or adverse events is prevented, to an extent of any practical importance in clinical practice. Different types of pharmacogenetic studies may improve our understanding of the functional consequence of a genetic variant in the clinical setting. The use of intermediate phenotypes instead of broad outcome parameters such as drug response or remission might improve our knowledge on what exactly happens if an individual with a specific genotype takes a certain drug. Here, we review the potential impact of an integrated approach, including the assessment of intermediate phenotypes for the effect of genetic polymorphism, the monitoring of therapy progress, and response prediction in depression.
Gillis, N K; Patel, J N; Innocenti, F
More than 100 medications approved by the US Food and Drug Administration include pharmacogenetic biomarkers in the drug label, many with cancer indications referencing germ line DNA variations. With the advent of next-generation sequencing (NGS) and its rapidly increasing uptake into cancer research and clinical practice, an enormous amount of data to inform documented gene-drug associations will be collected that must be exploited to optimize patient benefit. This review focuses on the implementation of germ line cancer pharmacogenetics in clinical practice. Specifically, it discusses the importance of germ line variation in cancer and the role of NGS in pharmacogenetic discovery and implementation. In the context of a scenario in which massive amounts of NGS-based genetic information will be increasingly available to health stakeholders, this review explores the ongoing debate regarding the threshold of evidence necessary for implementation, provides an overview of recommendations in cancer by professional organizations and regulatory bodies, and discusses limitations of current guidelines and strategies to improve third-party coverage.
Gillis, Nancy K.; Patel, Jai N.; Innocenti, Federico
Over 100 FDA-approved medications include pharmacogenetic biomarkers in the drug label, many with cancer indications referencing germline DNA variations. With the advent of next-generation sequencing (NGS) and its rapidly increasing uptake into cancer research and clinical practice, an enormous amount of data to inform documented gene-drug associations will be collected, which must be exploited to optimize patient benefit. This state-of-the-art article focuses on the implementation of germline cancer pharmacogenetics into clinical practice. Specifically, it discusses the importance of germline variation in cancer and the role of NGS in pharmacogenetic discovery and implementation. In the context of a scenario where massive NGS-based genetic information will be increasingly available to health stakeholders, this review explores the ongoing debate over the threshold of evidence necessary for implementation, provides an overview of recommendations in cancer by professional organizations and regulatory bodies, discusses limitations of current guidelines and strategies to improve third-party coverage. PMID:24136381
Norbert, Paul W; Roses, Allen D
In recent debates on novel procedures of molecular medicine pharmacogenomics is attracting more and more attention as a genotype-based approach for improving safety and efficacy of the use of therapeutic substances. Promoted by basic knowledge generated in the field of medical genomics, facilitated by novel technological tools for mapping genetic variation in individuals, and supported by results of initial clinical studies linking specific genotypes to metabolic characteristics of individuals important for assessing drug response, procedures of pharmacogenetics and pharmacogenomics now are starting to impact significantly on clinical research and development and medical practice. In this situation assessing the goals, risk, and benefits of pharmacogenetics and pharmacogenomics is essential for the medically successful, ethically justifiable, and socially acceptable implementation of genotype-based diagnosis and pharmacotherapy. We discuss the current state of the art in pharmacogenetics and pharmacogenomics and introduce a model for evidence based assessment of its goals, risk, and benefits. We differentiate here between pragmatic and normative issues in the development of pharmacogenomics in order to contrast prevailing, insufficiently interest-based modes of public technology assessment with the evidence-based mode that can be established as part of clinical study design. Finally, we provide a framework for the analysis of social accountability that can be used for technology development and technology assessment with regard to pharmacogenomics in particular and molecular medicine in general.
Pharmacogenetics holds great potential for improving the effectiveness of treatment modalities in infectious diseases by taking into account the genetic determinants of both the host and infectious agents’ individuality. Better utilization of resources and improved therapeutic efficiency are the expected outcomes of personalized medicine using pharmacogenetic and pharmacogenomics information made available by technological advances. However, there has been growing concern in the clinical community regarding the evaluation of the true benefits of these approaches. This perception is partly due to the limited number and perceived poor quality of economic evaluations in this field, and initiatives aimed at harmonizing and communicating strategies improving the quality of these studies and their acceptance by the clinical community are greatly needed. This paper reviews current literature of economic evaluations of pharmacogenetics interventions guiding pharmacotherapy in infectious diseases. PubMed and the NHS Centre for Reviews and Dissemination databases were searched using a combination of five broad research terms related to pharmacogenetic approaches, and papers relative to economic evaluations of pharmacogenetic interventions in infectious diseases retained for further analysis. Using these criteria, a total of 14 papers were included in this review. The area of economic evaluation of pharmacogenetic interventions in infectious diseases remains understudied and would benefit from greater harmonization. The main weaknesses of evaluations reviewed in this paper seem to be represented by poor evidence of pharmacogenetic marker validation, inconsistencies in the selection of costs and utility included in the economic models and the choice of sensitivity analysis. All these factors limit the overall transparency of the studies, greater acceptance of their results and applicability to diverse and possibly resourcelimited environments where these approaches could be
van Willigen, John; Chadha, N K
This article presents a comparative analysis of the available research on the social networks of older persons in India. Most of this research has been done in North Indian cities. The research foci of the available studies include network size, core networks and beyond, life course changes in networks, impacts of residency in old-age homes, gender differences, and joint and nuclear family residence. This research is discussed in terms of its policy implications. Because the research demonstrates that social networks are important for the welfare of older Indians, one can conclude that social policy that encourages the maintenance of robust networks throughout the life course may be worth pursuing. One aspect of policy is discussed. The analysis of the relationship between social network and gender suggests that current policies that can be seen as supporting gender inequality in terms of property may have a negative impact on the networks of older women.
Howland, Robert H
To the extent that genetic factors are associated with the efficacy, tolerability, and safety of different drugs, pharmacogenetic tests may be used to personalize medication treatments for an individual. Pharmacogenetic tests, such as GeneSight Psychotropic and the Genecept Assay, are being marketed directly to patients and prescribers despite a relative lack of evidence to support their clinical validity or utility. Pharmacogenetic testing is potentially useful in certain clinical situations, but its usefulness will depend on the knowledge base of the prescriber to be able to interpret the findings for a particular patient. Proposed guidelines on laboratory developed tests will likely encourage, if not require, evidence for the clinical validity and utility of pharmacogenetic tests before they are approved for marketing.
Daray, Federico Manuel; Maffia, Paulo César; Rothlin, Rodolfo Pedro; Errasti, Andrea Emilse
Pharmacogenetics studies how genetic variation influences the response of patients to drugs. This discipline has a greater impact in those medical specialties that treat complex diseases in which the therapeutic response is insufficient and/or have high costs such as psychiatry. This is a narrative review in which we analyze the main results of pharmacogenetic studies performed with the most relevant groups of psychoactive drugs and discusses missing for incorporating these advances into our daily practice. We conclude that despite the remarkable progress in the field of Pharmacogenetics in the last 10 years, studies in psychiatry have been inconclusive and the clinical use of pharmacogenetic testing is still limited. However, there are some encouraging elements about the applicability of these tools for the improvement of psychiatric treatments.
Mills, Rachel; Voora, Deepak; Peyser, Bruce; Haga, Susanne B
Pharmacogenetic testing refers to a type of genetic test to predict a patient’s likelihood to experience an adverse event or not respond to a given drug. Despite revision to several labels of commonly prescribed drugs regarding the impact of genetic variation, the use of this testing has been limited in many settings due to a number of factors. In the primary care setting, the limited office time as well as the limited knowledge and experience of primary care practitioners have likely attributed to the slow uptake of pharmacogenetic testing. This paper provides talking points for primary care physicians to discuss with patients when pharmacogenetic testing is warranted. As patients and physicians become more familiar and accepting of pharmacogenetic testing, it is anticipated that discussion time will be comparable to that of other clinical tests. PMID:24101877
2014 Carnegie Mellon University Fall 2014 SEI Research Review Malware Distribution Networks Software Engineering Institute Carnegie Mellon...DATES COVERED 4. TITLE AND SUBTITLE Fall 2014 SEI Research Review Malware Distribution Networks 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c...Project Description Create an approach to graph the topological structure of a domain name based malware distribution network (MDN) by leveraging
Hodgson, Naomi; Standish, Paul
Educational research as an academic field can be understood as a network or group of networks and, therefore, to consist of interconnected nodes that structure the way the field operates and understands its purpose. This paper deals with the nature of the induction of postgraduate students into the network of educational research that takes place…
Mooser, V; Waterworth, D M; Isenhour, T; Middleton, L
In the past pharmacological agents have contributed to a significant reduction in age-adjusted incidence of cardiovascular events. However, not all patients treated with these agents respond favorably, and some individuals may develop side-effects. With aging of the population and the growing prevalence of cardiovascular risk factors worldwide, it is expected that the demand for cardiovascular drugs will increase in the future. Accordingly, there is a growing need to identify the 'good' responders as well as the persons at risk for developing adverse events. Evidence is accumulating to indicate that responses to drugs are at least partly under genetic control. As such, pharmacogenetics - the study of variability in drug responses attributed to hereditary factors in different populations - may significantly assist in providing answers toward meeting this challenge. Pharmacogenetics mostly relies on associations between a specific genetic marker like single nucleotide polymorphisms (SNPs), either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Recently, for instance, associations have been reported between specific alleles of the apoE gene and the lipid-lowering response to statins, or the lipid-elevating effect of isotretinoin. Thus far, these types of studies have been mostly limited to a priori selected candidate genes due to restricted genotyping and analytical capacities. Thanks to the large number of SNPs now available in the public domain through the SNP Consortium and the newly developed technologies (high throughput genotyping, bioinformatics software), it is now possible to interrogate more than 200,000 SNPs distributed over the entire human genome. One pharmacogenetic study using this approach has been launched by GlaxoSmithKline to identify the approximately 4% of
In a globalized economy, education and research are becoming increasing international in content and context. Academic and research institutions worldwide try to internationalize their programs by setting formal or informal collaborations. An education that is enhanced by international experiences leads to mobility of the science and technology workforce. Existing academic cultures and research structures are at odds with efforts to internationalize education. For the past 20-30 years, the US has recognized the need to improve the abroad experience of our scientists and technologists: however progress has been slow. Despite a number of both federally and privately supported programs, efforts to scale up the numbers of participants have not been satisfactory. The exchange is imbalanced as more foreign scientists and researchers move to the US than the other way around. There are a number of issues that contribute to this imbalance but we could consider the US academic career system, as defined by its policies and practices, as a barrier to internationalizing the early career faculty experience. Strict curricula, pre-tenure policies and financial commitments discourage students, post doctoral fellows and pre-tenure faculty from taking international leaves to participate in research abroad experiences. Specifically, achieving an international experience requires funding that is not provided by the universities. Furthermore, intellectual property requirements and constraints in pre-tenure probationary periods may discourage students and faculty from collaborations with peers across the Atlantic or Pacific or across the American continent. Environments that support early career networking are not available. This presentation will discuss the increasing need for international collaborations and will explore the need for additional programs, more integration, better conditions and improved infrastructures that can encourage and support mobility of scientists. In addition
Networks are frequently cited as an important knowledge mobilization strategy; however, there is little empirical research that considers how they connect research and practice. Taking a social network perspective, I explore how central office personnel find, understand and share research knowledge within a research brokering network. This mixed…
Schuur, E. A.; McGuire, A. D.; Canadell, J.; Harden, J. W.; Kuhry, P.; Romanovsky, V. E.; Turetsky, M. R.; Schädel, C.
Approximately 1700 Pg (billion tons) of soil carbon are stored in the northern circumpolar permafrost zone, more than twice as much carbon than currently contained in the atmosphere. Permafrost thaw, and the microbial decomposition of previously frozen organic carbon, is considered one of the most likely positive feedbacks from terrestrial ecosystems to the atmosphere in a warmer world. Yet, the rate and form of release is highly uncertain but crucial for predicting the strength and timing of this carbon cycle feedback this century and beyond. Here we report on the formation of a new research coordination network (RCN) whose objective is to link biological C cycle research with well-developed networks in the physical sciences focused on the thermal state of permafrost. We found that published literature in the Science Citation Index identified with the search terms 'permafrost' and 'carbon' have increased dramatically in the last decade. Of total publications including those keywords, 86% were published since 2000, 65% since 2005, and 36% since 2008. Interconnection through this RCN is designed to produce new knowledge through research synthesis that can be used to quantify the role of permafrost carbon in driving climate change in the 21st century and beyond. An expert elicitation conducted as part of the RCN activities revealed that the total effect of carbon release from permafrost zone soils on climate is expected to be up to 30-46 Pg C over the next three decades, reaching 242-324 Pg C by 2100 and potentially up to 551-710 Pg C over the next several centuries under the strongest warming scenario presented to the group. These values, expressed in billions of tons of C in CO2 equivalents, combine the effect of C released both as CO2 and as CH4 by accounting for the greater heat-trapping capacity of CH4. Much of the actual C release by weight is expected to be in the form of CO2, with only about 3.5% of that in the form of CH4. However, the higher global warming
Wasserman, Richard; Serwint, Janet R; Kuppermann, Nathan; Srivastava, Rajendu; Dreyer, Benard
The Academic Pediatric Association (APA, formerly the Ambulatory Pediatric Association) first encouraged multi-institutional collaborative research among its members over 30 years ago. Individual APA members subsequently went on to figure prominently in establishing formal research networks. These enduring collaborations have been established to conduct investigations in a variety of generalist contexts. At present, 4 generalist networks--Pediatric Research in Office Settings (PROS), the Pediatric Emergency Care Applied Research Network (PECARN), the COntinuity Research NETwork (CORNET), and Pediatric Research in Inpatient Settings (PRIS)--have a track record of extensive achievement in generating new knowledge aimed at improving the health and health care of children. This review details the history, accomplishments, and future directions of these networks and summarizes the common themes, strengths, challenges, and opportunities inherent in pediatric generalist network research. Copyright © 2011 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.
Liu, John S.; Ho, Mei Hsiu-Ching; Lu, Louis Y. Y.
The body of literature addressing the phenomenon related to social networking services (SNSs) has grown rather fast recently. Through a systematic and quantitative approach, this study identifies the recent SNS research themes, which are the issues discussed by a coherent and growing subset of this literature. A set of academic articles retrieved from the Web of Science database is used as the basis for uncovering the recent themes. We begin the analysis by constructing a citation network which is further separated into groups after applying a widely used clustering method. The resulting clusters all consist of articles coherent in citation relationships. This study suggests eight fast growing recent themes. They span widely encompassing politics, romantic relationships, public relations, journalism, and health. Among them, four focus their issues largely on Twitter, three on Facebook, and one generally on both. While discussions on traditional issues in SNSs such as personality, motivations, self-disclosure, narcissism, etc. continue to lead the pack, the proliferation of the highlighted recent themes in the near future is very likely to happen. PMID:28107541
Alcohol addiction is one of the most common and devastating diseases in the world. Given the tremendous heterogeneity of alcohol-addicted individuals, it is unlikely that one medication will help nearly all patients. Thus, there is a clear need to develop predictors of response to existing medications. Naltrexone is a μ-opioid receptor antagonist, which has been approved in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in part because of noncompliance, but many patients do not respond despite high levels of compliance. There are reports that a missense single nucleotide polymorphism (rs179919 or A118G) in the μ-opioid receptor gene predicts a favorable response to naltrexone if an individual carries a “G” allele. This work will review the evidence for this hypothesis. The data are promising that the “G” allele predisposes to a beneficial naltrexone response among alcohol-addicted persons, but additional research is needed to prove this hypothesis in prospective clinical trials. PMID:23729643
Justin Stebbing is a member of the Royal College of Physicians, American Board of Internal Medicine and the Royal College of Pathologists. Originally, Justin trained in medicine at Trinity College Oxford (Oxford, UK), obtaining a triple first class degree. After completion of junior doctor posts in Oxford, he undertook a residency (junior doctor) training at The Johns Hopkins Hospital (MD, USA), before returning to London to continue his training in oncology at The Royal Marsden. Justin then undertook a PhD, funded by the medical research council, investigating the interplay between the immune system and cancer. Specifically, the role of heat shock proteins in tumorigenesis was examined, leading to the development of a cancer vaccine that is currently in clinical trials. Justin has published over 200 papers and book chapters, in journals such as the Lancet, New England Journal, Blood, the Journal of Clinical Oncology and Annals of Internal Medicine, the majority as first or last author. They mainly focus on early and late stage trials of new drugs, mechanisms of disease and prognostic indicators. He is on the editorial board of a number of journals and regularly serves as a referee. Justin's main focus is now in breast cancer, and helping patients with early and late stage disease get better.
Zornes, Deborah; Ferkins, Lesley; Piggot-Irvine, Eileen
The focus of this paper is to share thinking about networks in action research (AR) and to consider their role, purpose, and how networks' outcomes and impacts might be evaluated. Networks are often a by-product of AR projects, yet research focused on the network itself as part of a project is rare. The paper is one of several associated with the…
Zornes, Deborah; Ferkins, Lesley; Piggot-Irvine, Eileen
The focus of this paper is to share thinking about networks in action research (AR) and to consider their role, purpose, and how networks' outcomes and impacts might be evaluated. Networks are often a by-product of AR projects, yet research focused on the network itself as part of a project is rare. The paper is one of several associated with the…
Roberts, Rebecca L; Stamp, Lisa K
Gout is one of the most common forms of arthritis and the prevalence is increasing. Management comprises rapid and effective control of the inflammation in acute gout and sustained urate lowering in the long term. Improving the outcomes for cheaper old drugs and for the increasing number of new, more expensive agents is an important clinical goal. The role of pharmacogenetics in predicting response and adverse events to gout therapies is of considerable interest. Currently, prospective screening is employed to detect HLA-B*5801 carriage and glucose-6-phosphate dehydrogenase deficiency, to minimize occurrence of allopurinol hypersensitivity and pegloticase-related hemolytic anemia. In the future it is likely that other genetic markers of drug response will make the transition to clinical practice to further improve the efficacy and safety of gout therapies. In this review, we will examine the potential clinical relevance of specific genetic variants in the management of gout.
Pharmacogenetics (PGX) is the study of how genetic variants influence individual responses to drugs. Although numerous candidate gene studies in epilepsy PGX have been published, to date only two validated associations exist: the association of the *2 and *3 alleles of CYP2C9 with phenytoin metabolism and the association of HLA-B*1502 with serious hypersensitivity reactions to carbamazepine. The advent of novel technologies such as genomewide association studies and next generation sequencing will likely lead to the identification of additional genetic biomarkers. The potential benefits of epilepsy PGX are multiple: epilepsy treatment in individual patients would become more rationalized, clinical trials could be stratified according to patients' genetic profiles and novel therapeutic pathways may be uncovered. Ultimately, it is hoped that PGX will improve the quality of life for people suffering from epilepsy worldwide.
Sim, Sarah C.; Altman, Russ B.; Ingelman-Sundberg, Magnus
In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field. PMID:21309040
Fricke-Galindo, I; Jung-Cook, H; LLerena, A; López-López, M
Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients' quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.
Claudio-Campos, Karla; Orengo-Mercado, Carmelo; Renta, Jessicca Y.; Peguero, Muriel; García, Ricardo; Hernández, Gabriel; Corey, Susan; Cadilla, Carmen L.; Duconge, Jorge
Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island. PMID:26501165
Bosch, Luis Ángel Bermúdez
Warfarin is the current standard of care in oral anticoagulation therapy. It is commonly prescribed to treat venous thromboembolism, pulmonary embolism, acute myocardial infarction, and to decrease the risk of stroke in atrial fibrillation. Warfarin therapy is challenging because of marked and often unpredictable inter-individual dosing variations that effectively reach and maintain adequate anticoagulation. Several researchers have developed pharmacogenetic-guided maintenance dose algorithms that incorporate genetics and individual patient characteristics. However, there is limited information available concerning dosing during warfarin initiation. This is considered the most clinically challenging therapeutic phase. In such, the risk of recurrent thromboembolism and hemorrhage are elevated. The objective of this retrospective study is to predict the individual initial doses for Puerto Rican patients (n=175) commencing anticoagulation therapy at Veterans Affairs Caribbean Healthcare System (VACHS) using pharmacogenetic/pharmacokinetic-driven model. A pharmacogenetic driven model (R2=0.4809) was developed in Puerto Rican patients and combined with pharmacokinetic formulas that enabled us to predict the individual initial doses for patients (n=121) commencing anticoagulation therapy. WinNonlin® pharmacokinetic-pharmacodynamic simulations were carried out to determine the predictability of this model. This model demonstrated promising results with few (n=10) simulations outside of their respective therapy range. A customized pharmacogenetic-based warfarin maintenance dose algorithm (R2=0.7659) was developed in a derivation cohort of 131 patients. The predictability of this developed pharmacogenetic algorithm was compared with the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm and it demonstrated superior predictability within our study population. PMID:25285240
Schädel, C.; Schuur, E. A. G.; McGuire, A. D.; Canadell, J. G.; Harden, J.; Kuhry, P.; Romanovsky, V. E.; Turetsky, M. R.
Approximately 1700 Pg of soil carbon are stored in the northern circumpolar permafrost zone, more than twice as much carbon than currently contained in the atmosphere. Permafrost thaw, and the microbial decomposition of previously frozen organic carbon, is considered one of the most likely positive feedbacks from terrestrial ecosystems to the atmosphere in a warmer world. Yet, the rate and form of release is highly uncertain but crucial for predicting the strength and timing of this carbon cycle feedback this century and beyond. Here we report on the first products of a new research coordination network (RCN) whose objective is to link biological C cycle research with well-developed networks in the physical sciences focused on the thermal state of permafrost. We found that published literature in the Science Citation Index identified with the search terms 'permafrost' and 'carbon' have increased dramatically in the last decade. Of total publications including those keywords, 86% were published since 2000, 65% since 2005, and 36% since 2008. The first RCN activity consisted of an expert elicitation that revealed the total effect of carbon release from permafrost zone soils in climate is expected to be up to 30-46 Pg C over the next three decades, reaching 242-324 Pg C by 2100 and potentially up to 551-710 Pg C over the next several centuries under the strongest warming scenario presented to the group. These values, expressed in billions of tons of C in CO2 equivalents, combine the effect of C released both as CO2 and as CH4 by accounting for the greater heat-trapping capacity of CH4. However, the higher global warming potential of CH4 means that almost half of the effect of future permafrost zone carbon emissions on climate forcing was expected by this group to be a result of CH4 emissions from wetlands, lakes, and other oxygen-limited environments where organic matter will be decomposing. These results demonstrate the vulnerability of organic C stored in near
Wasserman, Richard; Serwint, Janet R.; Kuppermann, Nathan; Srivastava, Rajendu; Dreyer, Benard
The Academic Pediatric Association (APA – formerly the Ambulatory Pediatric Association) first encouraged multi-institutional collaborative research among its members over thirty years ago. Individual APA members went on subsequently to figure prominently in establishing formal research networks. These enduring collaborations have been established to conduct investigations in a variety of generalist contexts. At present, four generalist networks – Pediatric Research in Office Settings (PROS), the Pediatric Emergency Care Applied Network (PECARN), the COntinuity Research NETwork (CORNET), and Pediatric Research in Inpatient Settings (PRIS) – have a track record of extensive achievement in generating new knowledge aimed at improving the health and health care of children. This review details the history, accomplishments, and future directions of these networks and summarizes the common themes, strengths, challenges and opportunities inherent in pediatric generalist network research. PMID:21282083
Belza, Basia; Altpeter, Mary; Smith, Matthew Lee; Ory, Marcia G
As the first Centers for Disease Control and Prevention (CDC) Prevention Research Centers Program thematic network, the Healthy Aging Research Network was established to better understand the determinants of healthy aging within older adult populations, identify interventions that promote healthy aging, and assist in translating research into sustainable community-based programs throughout the nation. To achieve these goals requires concerted efforts of a collaborative network of academic, community, and public health organizational partnerships. For the 2001-2014 Prevention Research Center funding cycles, the Healthy Aging Research Network conducted prevention research and promoted the wide use of practices known to foster optimal health. Organized around components necessary for successful collaborations (i.e., governance and infrastructure, shaping focus, community involvement, and evaluation and improvement), this commentary highlights exemplars that demonstrate the Healthy Aging Research Network's unique contributions to the field. The Healthy Aging Research Network's collaboration provided a means to collectively build capacity for practice and policy, reduce fragmentation and duplication in health promotion and aging research efforts, maximize the efficient use of existing resources and generate additional resources, and ultimately, create synergies for advancing the healthy aging agenda. This collaborative model was built upon a backbone organization (coordinating center); setting of common agendas and mutually reinforcing activities; and continuous communications. Given its successes, the Healthy Aging Research Network model could be used to create new and evaluate existing thematic networks to guide the translation of research into policy and practice.
This special report concerns a talk on data standards given at a workshop entitled 'An International Perspective on Pharmacogenetics: The Intersections between Innovation, Regulation and Health Delivery', which was held by the Organization for Economic Co-operation and Development (OECD) on October 17-19, 2005, in Rome, Italy. The worlds of healthcare and life sciences (HCLS) are extremely fragmented in terms of their underlying information technology, making it difficult to semantically exchange information between disparate entities. While we have reached the point where functional interoperability is ubiquitous, we are still far from achieving true semantic interoperability where a receiving system can use incoming data as though it was created internally. The critical enablers of semantic interoperability are information standards dedicated to HCLS data, spanning all the way from biological research data to clinical research and clinical trials, and finally to healthcare clinical data. The challenge lies in integrating various data standards based on predetermined goals, thereby improving the quality of care provided to patients.
Maggo, Simran D S; Kennedy, Martin A; Clark, David W J
The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its
Holmes, Michael V.; Shah, Tina; Vickery, Christine; Smeeth, Liam
Background Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics). Objectives We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research. Data Sources Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. Study Eligibility Criteria, Participants, and Intervention Criteria We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans. Study Appraisal and Synthesis Methods Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study. Results From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25∶1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40–222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of ≥4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were
Ambite, Jose Luis; Ames, Joseph; Ananthakrishnan, Rachana; Burns, Gully; Chervenak, Ann L; Foster, Ian; Liming, Lee; Keator, David; Macciardi, Fabio; Madduri, Ravi; Navarro, John-Paul; Potkin, Steven; Rosen, Bruce; Ruffins, Seth; Schuler, Robert; Turner, Jessica A; Toga, Arthur; Williams, Christina; Kesselman, Carl
Objective As biomedical technology becomes increasingly sophisticated, researchers can probe ever more subtle effects with the added requirement that the investigation of small effects often requires the acquisition of large amounts of data. In biomedicine, these data are often acquired at, and later shared between, multiple sites. There are both technological and sociological hurdles to be overcome for data to be passed between researchers and later made accessible to the larger scientific community. The goal of the Biomedical Informatics Research Network (BIRN) is to address the challenges inherent in biomedical data sharing. Materials and methods BIRN tools are grouped into ‘capabilities’ and are available in the areas of data management, data security, information integration, and knowledge engineering. BIRN has a user-driven focus and employs a layered architectural approach that promotes reuse of infrastructure. BIRN tools are designed to be modular and therefore can work with pre-existing tools. BIRN users can choose the capabilities most useful for their application, while not having to ensure that their project conforms to a monolithic architecture. Results BIRN has implemented a new software-based data-sharing infrastructure that has been put to use in many different domains within biomedicine. BIRN is actively involved in outreach to the broader biomedical community to form working partnerships. Conclusion BIRN's mission is to provide capabilities and services related to data sharing to the biomedical research community. It does this by forming partnerships and solving specific, user-driven problems whose solutions are then available for use by other groups. PMID:21515543
Johnson, J A; Caudle, K E; Gong, L; Whirl-Carrillo, M; Stein, C M; Scott, S A; Lee, M T; Gage, B F; Kimmel, S E; Perera, M A; Anderson, J L; Pirmohamed, M; Klein, T E; Limdi, N A; Cavallari, L H; Wadelius, M
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry. © 2017 American Society for Clinical Pharmacology and Therapeutics.
Lipman, Paula Darby; Lange, Carol J; Cohen, Rachel A; Peterson, Kevin A
Practice-based research networks may be expanding beyond research into rapid learning systems. This mixed-methods study uses Agency for Healthcare Research and Quality registry data to identify networks currently engaged in dissemination of research findings and to select a sample to participate in qualitative semistructured interviews. An adapted Diffusion of Innovations framework was used to organize concepts by characteristics of networks, dissemination activities, and mechanisms for rapid learning. Six regional networks provided detailed information about dissemination strategies, organizational context, role of practice-based research network, member involvement, and practice incentives. Strategies compatible with current practices and learning innovations that generate observable improvements may increase effectiveness of rapid learning approaches.
Zhang, Xin; Song, Ding-Li; Yan, Shu
Digital library is a self-development needs for the modern library to meet the development requirements of the times, changing the way services and so on. digital library from the hardware, technology, management and other aspects to objective analysis of the factors of threats to digital library network security. We should face up the problems of digital library network security: digital library network hardware are "not hard", the technology of digital library is relatively lag, digital library management system is imperfect and other problems; the government should take active measures to ensure that the library funding, to enhance the level of network hardware, to upgrade LAN and prevention technology, to improve network control technology, network monitoring technology; to strengthen safety management concepts, to prefect the safety management system; and to improve the level of security management modernization for digital library.
Sicard, M.; D'Amico, G.; Comerón, A.; Mona, L.; Alados-Arboledas, L.; Amodeo, A.; Baars, H.; Baldasano, J. M.; Belegante, L.; Binietoglou, I.; Bravo-Aranda, J. A.; Fernández, A. J.; Fréville, P.; García-Vizcaíno, D.; Giunta, A.; Granados-Muñoz, M. J.; Guerrero-Rascado, J. L.; Hadjimitsis, D.; Haefele, A.; Hervo, M.; Iarlori, M.; Kokkalis, P.; Lange, D.; Mamouri, R. E.; Mattis, I.; Molero, F.; Montoux, N.; Muñoz, A.; Muñoz Porcar, C.; Navas-Guzmán, F.; Nicolae, D.; Nisantzi, A.; Papagiannopoulos, N.; Papayannis, A.; Pereira, S.; Preißler, J.; Pujadas, M.; Rizi, V.; Rocadenbosch, F.; Sellegri, K.; Simeonov, V.; Tsaknakis, G.; Wagner, F.; Pappalardo, G.
In the framework of ACTRIS (Aerosols, Clouds, and Trace Gases Research Infrastructure Network) summer 2012 measurement campaign (8 June-17 July 2012), EARLINET organized and performed a controlled exercise of feasibility to demonstrate its potential to perform operational, coordinated measurements and deliver products in near-real time. Eleven lidar stations participated in the exercise which started on 9 July 2012 at 06:00 UT and ended 72 h later on 12 July at 06:00 UT. For the first time, the single calculus chain (SCC) - the common calculus chain developed within EARLINET for the automatic evaluation of lidar data from raw signals up to the final products - was used. All stations sent in real-time measurements of a 1 h duration to the SCC server in a predefined netcdf file format. The pre-processing of the data was performed in real time by the SCC, while the optical processing was performed in near-real time after the exercise ended. 98 and 79 % of the files sent to SCC were successfully pre-processed and processed, respectively. Those percentages are quite large taking into account that no cloud screening was performed on the lidar data. The paper draws present and future SCC users' attention to the most critical parameters of the SCC product configuration and their possible optimal value but also to the limitations inherent to the raw data. The continuous use of SCC direct and derived products in heterogeneous conditions is used to demonstrate two potential applications of EARLINET infrastructure: the monitoring of a Saharan dust intrusion event and the evaluation of two dust transport models. The efforts made to define the measurements protocol and to configure properly the SCC pave the way for applying this protocol for specific applications such as the monitoring of special events, atmospheric modeling, climate research and calibration/validation activities of spaceborne observations.
Comfere, Nneka I; Ikediobi, Ogechi N; Peters, Margot S; el-Azhary, Rokea A; Gibson, Lawrence E
The term pharmacogenetics is used to describe an evolving field that aims to understand the relationship between individual variations in genetic sequence and differences in the therapeutic and toxic response to medications. The promise of pharmacogenetics is empowerment of clinicians with information that will enable them to personalize drug therapy - to prescribe the right medication at the right dose for each patient, while minimizing adverse effects. Despite dramatic advances, wide application of pharmacogenetics to clinical practice has been slow for a number of reasons, including lack of evidence-based therapeutic guidelines as well as ethical concerns and cost. To illustrate applications to dermatology practice, we present three clinical scenarios that serve as a springboard for discussion of the principles of pharmacogenetics and how they can be used to guide treatment with azathioprine, 5-fluorouracil, and trastuzumab. The therapeutic and toxic effects of a given medication ultimately depend on its combined pharmacokinetic, pharmacodynamic, and pharmacogenetic properties in a given individual. Pharmacodynamic properties of individual medications must be correlated with single nucleotide polymorphisms. Test recommendations and standardization of therapy for specific disorders can then be established. © 2013 The International Society of Dermatology.
Nutescu, Edith A.; Drozda, Katarzyna; Bress, Adam P.; Galanter, William L.; Stevenson, James; Stamos, Thomas D.; Desai, Ankit A.; Duarte, Julio D.; Gordeuk, Victor; Peace, David; Kadkol, ShriHari S.; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A.; Garcia, Joe G.N.; Cavallari, Larisa H.
Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. PMID:23864527
Rodríguez-Vicente, Ana E; Lumbreras, Eva; Hernández, Jesus M; Martín, Miguel; Calles, Antonio; Otín, Carlos López; Algarra, Salvador Martín; Páez, David; Taron, Miquel
Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.
Yan, Li; Beckman, Robert
Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels ofHER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.
Fabbri, Chiara; Crisafulli, Concetta; Calabrò, Marco; Spina, Edoardo; Serretti, Alessandro
Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression. This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed. Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.
Ortega, V E
Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Can, Adem; Schulze, Thomas G.; Gould, Todd D.
Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium’s therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future. PMID:24534415
Lazinger, Susan S.
Describes ALEPH, the research library network in Israel, and analyzes the strengths and weaknesses of its decentralized structure. Highlights include comparisons between RLIN and ALEPH; centralized versus decentralized networks; the format of ALEPH; authority control in ALEPH; and non-Roman scripts in both networks. (16 references) (LRW)
Wu, Yanwen; Liu, Zehong; Zhou, Guangyue
With the development of mobile telecommunication network, users of CDMA advanced their request of network service quality. While the operators also change their network management object from signal coverage to performance improvement. In that case, reasonably layout & optimization of mobile telecommunication network, reasonably configuration of network resource, improvement of the service quality, and increase the enterprise's core competition ability, all those have been concerned by the operator companies. This paper firstly looked into the flow of CDMA network optimization. Then it dissertated to some keystones in the CDMA network optimization, like PN code assignment, calculation of soft handover, etc. As GSM is also the similar cellular mobile telecommunication system like CDMA, so this paper also made a contrast research of CDMA and GSM network optimization in details, including the similarity and the different. In conclusion, network optimization is a long time job; it will run through the whole process of network construct. By the adjustment of network hardware (like BTS equipments, RF systems, etc.) and network software (like parameter optimized, configuration optimized, capacity optimized, etc.), network optimization work can improve the performance and service quality of the network.
These vision preprocessor and ART autonomous classifier examples are just two of the many neural network architectures now being developed by...computational theories with natural realizations as real-time adaptive neural network architectures with promising properties for tackling some of the
Querci, F. R.; Querci, M.
Generally speaking, variable stars are monitored through observing campaigns which coordinate multi-site telescopes at various longitudes. A new practice is in progress: devoted networks involving robotic telescopes. We will review these two technologies and will emphasize the NORT (Network of Oriental Robotic Telescopes) project which we are promoting in North Africa, Middle-Eastern countries and Asia.
Ruaño, Gualberto; Seip, Richard; Windemuth, Andreas; Wu, Alan H B; Thompson, Paul D
Statin responsiveness is an area of great research interest given the success of the drug class in the treatment of hypercholesterolemia and in primary and secondary prevention of cardiovascular disease. Interrogation of the patient's genome for gene variants will eventually guide anti-hyperlipidemic intervention. In this review, we discuss methodological approaches to discover genetic markers predictive of class-wide and drug-specific statin efficacy and safety. Notable pharmacogenetic findings are summarized from hypothesis-free genome wide and hypothesis-led candidate gene association studies. Physiogenomic models and clinical decision support systems will be required for DNA-guided statin therapy to reach practical use in medicine.
Joshi, Gyanendra Prasad; Nam, Seung Yeob; Kim, Sung Won
A cognitive radio wireless sensor network is one of the candidate areas where cognitive techniques can be used for opportunistic spectrum access. Research in this area is still in its infancy, but it is progressing rapidly. The aim of this study is to classify the existing literature of this fast emerging application area of cognitive radio wireless sensor networks, highlight the key research that has already been undertaken, and indicate open problems. This paper describes the advantages of cognitive radio wireless sensor networks, the difference between ad hoc cognitive radio networks, wireless sensor networks, and cognitive radio wireless sensor networks, potential application areas of cognitive radio wireless sensor networks, challenges and research trend in cognitive radio wireless sensor networks. The sensing schemes suited for cognitive radio wireless sensor networks scenarios are discussed with an emphasis on cooperation and spectrum access methods that ensure the availability of the required QoS. Finally, this paper lists several open research challenges aimed at drawing the attention of the readers toward the important issues that need to be addressed before the vision of completely autonomous cognitive radio wireless sensor networks can be realized.
Joshi, Gyanendra Prasad; Nam, Seung Yeob; Kim, Sung Won
A cognitive radio wireless sensor network is one of the candidate areas where cognitive techniques can be used for opportunistic spectrum access. Research in this area is still in its infancy, but it is progressing rapidly. The aim of this study is to classify the existing literature of this fast emerging application area of cognitive radio wireless sensor networks, highlight the key research that has already been undertaken, and indicate open problems. This paper describes the advantages of cognitive radio wireless sensor networks, the difference between ad hoc cognitive radio networks, wireless sensor networks, and cognitive radio wireless sensor networks, potential application areas of cognitive radio wireless sensor networks, challenges and research trend in cognitive radio wireless sensor networks. The sensing schemes suited for cognitive radio wireless sensor networks scenarios are discussed with an emphasis on cooperation and spectrum access methods that ensure the availability of the required QoS. Finally, this paper lists several open research challenges aimed at drawing the attention of the readers toward the important issues that need to be addressed before the vision of completely autonomous cognitive radio wireless sensor networks can be realized. PMID:23974152
Johnston, Jeffrey S.; Bao, Shengying; Kelley, Katherine A.
Objective To develop a genotype exercise to improve pharmacy students’ comprehension of pharmacogenetic principles that apply to patient care. Design Deoxyribonucleic acid (DNA) was collected during class from 10 student volunteers and subjected to genotype analysis. The results were presented to the class and discussed in the context of a patient genetic counseling session. Students completed a survey instrument regarding their attitudes toward this learning experience. Assessment Students indicated that the exercise engaged them with the course content and would positively influence their ability to apply pharmacogenetic principles to patient care. Conclusion An applied genotype exercise enhanced learning of pharmacogenetic principles. Based on these findings, conducting a genotype exercise in a large classroom setting is feasible in terms of time and expense, and meaningful in terms of student satisfaction. PMID:19564986
Harrak, Mohammed; Khabbal, Youssef; Amarti, Afaf; El Hassouni, Mohammed; Ouldim, Karim
Drug response is often variable from one individual to another, which sometimes makes them difficult to use when the therapeutic range is narrow. This interindividual variability in response can be explained in part by genetic factors affecting the metabolism, transport and the mechanism of action of drugs. Pharmacogenetics studies the genetic mechanisms involved in the response to drugs in order to optimize drug therapy, both in terms of efficacy and job security. This article summarizes the most known present clinical applications that illustrate the benefit of pharmacogenetic tests available to the clinician and are feasible for routine therapeutic management of patients (prediction of efficacy and toxicity of drugs), but also to demonstrate the benefit of pharmacogenetic tests in terms of health economics (reducing the incidence of hospitalizations for adverse drug events).
Hagen, N.A.; Stiles, C.R.; Biondo, P.D.; Cummings, G.G.; Fainsinger, R.L.; Moulin, D.E.; Pereira, J.L.; Spice, R.
Background Within many health care disciplines, research networks have emerged to connect researchers who are physically separated, to facilitate sharing of expertise and resources, and to exchange valuable skills. A multicentre research network committed to studying difficult cancer pain problems was launched in 2004 as part of a Canadian initiative to increase palliative and end-of-life care research capacity. Funding was received for 5 years to support network activities. Methods Mid-way through the 5-year granting period, an external review panel provided a formal mid-grant evaluation. Concurrently, an internal evaluation of the network by survey of its members was conducted. Based on feedback from both evaluations and on a review of the literature, we identified several components believed to be relevant to the development of a successful clinical cancer research network. Results These common elements of successful clinical cancer research networks were identified: shared vision, formal governance policies and terms of reference, infrastructure support, regular and effective communication, an accountability framework, a succession planning strategy to address membership change over time, multiple strategies to engage network members, regular review of goals and timelines, and a balance between structure and creativity. Conclusions In establishing and conducting a multi-year, multicentre clinical cancer research network, network members were led to reflect on the factors that contributed most to the achievement of network goals. Several specific factors were identified that seemed to be highly relevant in promoting success. These observations are presented to foster further discussion on the successful design and operation of research networks. PMID:21980256
Wang, Kui; Fu, Xiufen
Based on the actual data of urban transport in Guangzhou, 19,150 bus stations in Guangzhou (as of 2014) are selected as nodes. Based on the theory of complex network, the network model of Guangzhou urban transport is constructed. By analyzing the degree centrality index, betweenness centrality index and closeness centrality index of nodes in the network, the level of centrality of each node in the network is studied. From a different point of view to determine the hub node of Guangzhou urban transport network, corresponding to the city's key sites and major transfer sites. The reliability of the network is determined by the stability of some key nodes (transport hub station). The research of network node centralization can provide a theoretical basis for the rational allocation of urban transport network sites and public transport system planning.
Daugherty, Sarah E; Wahba, Sarita; Fleurence, Rachael
The Patient-Centered Outcomes Research Institute (PCORI) recently launched PCORnet to establish a single inter-operable multicenter data research network that will support observational research and randomized clinical trials. This paper provides an overview of the patient-powered research networks (PPRNs), networks of patient organizations focused on a particular health condition that are interested in sharing health information and engaging in research. PPRNs will build on their foundation of trust within the patient communities and draw on their expertise, working with participants to identify true patient-centered outcomes and direct a patient-centered research agenda. The PPRNs will overcome common challenges including enrolling a diverse and representative patient population; engaging patients in governance; designing the data infrastructure; sharing data securely while protecting privacy; prioritizing research questions; scaling small networks into a larger network; and identifying pathways to sustainability. PCORnet will be the first distributed research network to bring PCOR to national scale. PMID:24821741
Randall, Melinda; Albein-Urios, Natalia; Brignell, Amanda; Gulenc, Alisha; Hennel, Sabine; Coates, Cathy; Symeonides, Christos; Hiscock, Harriet; Marraffa, Catherine; Silove, Natalie; Bayl, Vivian; Woolfenden, Susan; Williams, Katrina
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with reported prevalence of more than 1/100. In Australia, paediatricians are often involved in diagnosing ASD and providing long-term management. However, it is not known how paediatricians diagnose ASD. This study aimed to investigate whether the way Australian paediatricians diagnose ASD is in line with current recommendations. Members of the Australian Paediatric Research Network were invited to answer questions about their ASD diagnostic practice in a multi-topic survey and also as part of a study about parents needs around the time of a diagnosis of ASD. The majority of the 124 paediatricians who responded to the multi-topic survey and most who responded to the parent needs survey reported taking more than one session to make a diagnosis of ASD. Most paediatricians included information from preschool, child care or school when making a diagnosis, and over half included information from speech pathology or psychology colleagues more than 50% of the time. The main reasons for not including assessment information in the diagnostic process were service barriers such as no regular service available or long waiting lists. More than 70% reported ordering audiology and genetic tests more than half of the time. Not all paediatricians are following current recommendations for diagnosing ASD more than 50% of the time. While there are good reasons why current diagnostic approaches may fall short of expected standards, these need to be overcome to ensure diagnostic validity and optimal services for all children and their families. © 2016 The Authors. Journal of Paediatrics and Child Health © 2016 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
Lu, Da-Yong; Lu, Ting-Ren; Xu, Bin; Ding, Jian
‘Pharmacogenetics or Pharmacogenomics’ (PG) is one of the most practiced cancer therapeutic strategies, tailored for individualized patients. Despite its popularity and rapid advancements in the field, many obstacles for cancer therapy PG still need to be overcome. By borrowing scientific systems from other disciplines such as cancer diagnosis, and therapeutic information from the diversity of tumor origins, categories and stages, cancer therapy PG may hopefully be improved. Furthermore, to quickly acquire genetic and pathologic information and seek therapeutic interventions, possible breakthroughs may come from beyond – changing the cancer therapeutic landscapes. The next generations of PG protocols and hospital routines for searching deadly cancer pathogenic pathways versus drug-targeting predictions are of great clinical significance for the future. Yet, progress of cancer therapy PG is entering into a bottleneck stage owing to simple model of relevant techniques and routines. Promoting or even innovating present PG modular is very necessary. This perspective highlights this issue by introducing new initiatives and ideas. PMID:28031929
Džoljić, Eleonora; Novaković, Ivana; Krajinovic, Maja; Grbatinić, Ivan; Kostić, Vladimir
Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.
Dulucq, Stéphanie; Laverdière, Caroline; Sinnett, Daniel; Krajinovic, Maja
Advances in our understanding of the pathobiology of childhood acute lymphoblastic leukemia (ALL) have led to risk-targeted treatment regimens and remarkable improvement in survival rates. Still, up to 20% of patients experience treatment failure due to drug resistance. Treatment-related toxicities are often life-threatening and are the primary cause of treatment interruption, while ALL survivors may develop complications due to exposure to chemotherapy and/or irradiation during a vulnerable period of development. Different factors may contribute to variable treatment outcomes including patient genetics that has been shown to play important role. This review summarizes candidate gene and genome-wide association studies that identified common polymorphisms underlying variability in treatment responses including a few studies addressing late effects of the treatment. Genetic variants influencing antileukemic drug effects or leukemic cell biology have been identified, including for example variants in folate-dependent enzymes, influx and efflux transporters, metabolizing enzymes, drug receptor or apoptotic proteins. Many pharmacogenetic studies have been conducted in ALL and a variety of potential markers have been identified. Yet more comprehensive insight into genome variations influencing drug responses is needed. Whole exome/genome sequencing, careful study design, mechanistic explanation of association found and collaborative studies will ultimately lead to personalized treatment and improved therapeutic and health outcomes.
Brennan, Mark D
This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype. Among pharmacokinetic markers, CYP2D6 metabolizer phenotype has clear clinical significance, as it impacts dosing considerations for aripiprazole, iloperidone and risperidone, and variants of the ABCB1 gene hold promise as biomarkers for dosing for olanzapine and clozapine. Among pharmacodynamic variants, the TaqIA1 allele of the DRD2 gene, the DRD3 (Ser9Gly) polymorphism, and the HTR2C -759C/T polymorphism have emerged as potential biomarkers for response and/or side effects. However, large-scale candidate gene studies and genome-wide association studies indicate that pharmacotypic genes may ultimately prove to be the richest source of biomarkers for response and side effect profiles for second-generation antipsychotics.
Herranz, J L
Despite the large number of antiepileptic drugs (AED) currently on the market, in 20-30% of patients it is still not possible to achieve a total control of the seizures or to prevent the appearance of idiosyncratic side effects. In this study the pharmacokinetic and pharmacodynamic factors involved in pharmacoresistance in epilepsies are analysed, with special attention given to the polymorphisms of metabolising enzymes or their inducers, particularly the hepatic cytochrome CYP, the over-expression of membrane-transporting proteins -P-glycoprotein (PGP), MRP- and polymorphisms in the ion channels. Idiosyncratic effects are produced due to an imbalance between the production of toxic metabolites and the individual capacity to detoxify them. Pharmacogenetics and pharmacogenomics can identify certain personal, biochemical, enzymatic and genetic characteristics that are of use in selecting the most effective AED with the lowest risk of idiosyncratic effects for each person. Although new AED that can help reduce the number of medication resistant patients must be introduced, at the same other therapeutic strategies have to be developed with the aid of pharmacogenomics; more specifically there is a need for AED that are not transported by PGP o MRP, or substances that antagonise those membrane transporters and make it possible for the AED to reach the site where they are to act. Furthermore, the detoxification capacity of each individual must be known in order to be able to minimise the risk of idiosyncratic side effects.
Eugster, W.; Zeeman, M. J.; Häsler, R.; Buchmann, N.
Within CarboEurope more than 100 eddy covariance flux towers aim at providing spatially representative CO2 and energy fluxes from the major forest ecosystem types, grasslands, and croplands. Still, at the regional (10's of km) scale the spatial variation in topography and ecosystem types is not adequately represented in mountainous areas such as Switzerland. Therefore we have extended the cluster of three CarboEurope flux sites (Oensingen grassland; Oensingen cropland; Laegeren mixed forest) by additional sites that form an elevational transect from the low elevations of the Swiss Plateau (around 400 m a.s.l.) to the interior of the Central Alps (around 2000 m a.s.l.). As of 2006 there were the following sites operated by this research group: Elevation Ecosystem Location Since Type 2000 m Alpine pasture Crap Alv ETH 2005 seasonal 1640 m Subalpine coniferous forest Davos 1997 continuous 1000 m Montane Grassland Früebüel ETH 2006 continuous 0700 m Montane mixed forest Lägeren 2004 continuous 0400 m Lowland Grassland Chamau ETH 2006 continuous 0400 m Cropland Oensingen 2004 continuous In addition to the CarboEurope network design these sites attempt to cover all agriculturally important ecosystems in Switzerland, which are characterized by a seasonal three-stage management system where cattle are moved from their winter pastures in the lowlands to the montane meadows in spring, followed by the summer pastures above the treeline in the Alps. At the same time the two forest sites cover the two most important types with deciduous trees (beech, maple, ash) dominated mixed forest at lower elevations, and Norway spruce near the Alpine treeline. The long-term flux research to be carried out along this elevational transect will allow us to gain a better understanding of how elevation---and thus a very steep climate gradient over a relatively short horizontal distance---interrelate with land use and land management. This will greatly help to increase our ability to predict
Kratochvil, D.; Sood, D.
The future telecommunications capacity and connectivity requirements of the United States (US) research and development (R&D) community raise two concerns. First, would there be adequate privately-owned communications capacity to meet the ever-increasing requirements of the US R&D community for domestic and international connectivity? Second, is the method of piecemeal implementation of communications facilities by individual researchers cost effective when viewed from an integrated perspective? To address the capacity issue, Contel recently completed a study for NASA identifying the current domestic R&D telecommunications capacity and connectivity requirements, and projecting the same to the years 1991, 1996, 2000, and 2010. The work reported here extends the scope of an earlier study by factoring in the impact of international connectivity requirements on capacity and connectivity forecasts. Most researchers in foreign countries, as is the case with US researchers, rely on regional, national or continent-wide networks to collaborate with each other, and their US counterparts. The US researchers' international connectivity requirements, therefore, stem from the need to link the US domestic research networks to foreign research networks. The number of links and, more importantly, the speeds of links are invariably determined by the characteristics of the networks being linked. The major thrust of this study, therefore, was to identify and characterize the foreign research networks, to quantify the current status of their connectivity to the US networks, and to project growth in the connectivity requirements to years 1991, 1996, 2000, and 2010 so that a composite picture of the US research networks in the same years could be forecasted. The current (1990) US integrated research network, and its connectivity to foreign research networks is shown. As an example of projections, the same for the year 2010 is shown.
Peckham, Stephen; Hutchison, Brian
The performance of Canada's primary care sector remains lacklustre relative to other wealthy industrialized countries, and it has been suggested that a lack of investment in research and evaluation may be a cause. One approach to improving and sustaining primary care research is through research networks. Over the past few years, significant investments have begun to be made in developing primary care networks in Canada. While Canadian experience in this area is relatively new, in the United Kingdom primary care research networks were first established in the 1980s. Initially developed at a local level, these have more recently been incorporated into large-scale national networks. This paper reviews the UK experience and highlights potential lessons for the development of networks in Canada. PMID:23968616
Eaton, Carrie Diaz; Allen, Deborah; Anderson, Laurel J.; Bowser, Gillian; Pauley, Mark A.; Williams, Kathy S.; Uno, Gordon E.
The first summit of projects funded by the National Science Foundation’s Research Coordination Networks for Undergraduate Biology Education (RCN-UBE) program was held January 14–16, 2016, in Washington, DC. Sixty-five scientists and science educators from 38 of the 41 Incubator and Full RCN-UBE awards discussed the value and contributions of RCNs to the national biology education reform effort. The summit illustrated the progress of this innovative UBE track, first awarded in 2009. Participants shared experiences regarding network development and growth, identified best practices and challenges faced in network management, and discussed work accomplished. We report here on key aspects of network evaluation, characteristics of successful networks, and how to sustain and broaden participation in networks. Evidence from successful networks indicates that 5 years (the length of a Full RCN-UBE) may be insufficient time to produce a cohesive and effective network. While online communication promotes the activities of a network and disseminates effective practices, face-to-face meetings are critical for establishing ties between network participants. Creation of these National Science Foundation–funded networks may be particularly useful for consortia of faculty working to address problems or exchange novel solutions discovered while introducing active-learning methods and/or course-based research into their curricula.
Mao, Y. F.; Li, J. R.; Deng, L. J.
Automatically Switched Optical Network (ASON) is currently a new and hot research subject in the world. It can provide high bandwidth, high assembly flexibility, high network security and reliability, but with a low management cost. It is presented to meet the requirements for high-throughput optical access with stringent Quality of Service (QoS). But as a brand new technology, ASON can not be supported by the traditional protocol software and network equipments. And the approach to build a new ASON network on the basis of completely abandoning the traditional optical network facilities is not desirable, because it costs too much and wastes a lot of network resources can also be used. So how to apply ASON to the current networks and realize the smooth transition between the existing network and ASON has been a serious problem to many network operators. In this research, the status in quo of ASON is introduced first and then the key problems should be considered when applying ASON to current networks are discussed. Based on this, the strategies should be complied with to overcome these key problems are listed. At last, the approach to apply ASON to the current optical networks is proposed and analyzed.
Werner, James J; Stange, Kurt C
Practice-based research networks (PBRNs) have developed a grounded approach to conducting practice-relevant and translational research in community practice settings. Seismic shifts in the health care landscape are shaping PBRNs that work across organizational and institutional margins to address complex problems. Praxis-based research networks combine PBRN knowledge generation with multistakeholder learning, experimentation, and application of practical knowledge. The catalytic processes in praxis-based research networks are cycles of action and reflection based on experience, observation, conceptualization, and experimentation by network members and partners. To facilitate co-learning and solution-building, these networks have a flexible architecture that allows pragmatic inclusion of stakeholders based on the demands of the problem and the needs of the network. Praxis-based research networks represent an evolving trend that combines the core values of PBRNs with new opportunities for relevance, rigor, and broad participation. © Copyright 2014 by the American Board of Family Medicine.
Werner, James J.; Stange, Kurt C.
Practice-based research networks (PBRNs) have developed a grounded approach to conducting practice-relevant and translational research in community practice settings. Seismic shifts in the healthcare landscape are shaping PBRNs that work across organizational and institutional margins to address complex problems. Praxis-based research networks combine PBRN knowledge generation with multi-stakeholder learning, experimentation, and practical knowledge application. The catalytic processes in praxis-based research networks are cycles of action and reflection based on experience, observation, conceptualization, and experimentation by network members and partners. To facilitate co-learning and solution-building, these networks have a flexible architecture that allows pragmatic inclusion of stakeholders based on demands of the problem and the needs of the network. Praxis-based research networks represent an evolving trend that combines the core values of PBRNs with new opportunities for relevance, rigor, and broad participation. PMID:25381067
Fleurence, Rachael L; Curtis, Lesley H; Califf, Robert M; Platt, Richard; Selby, Joe V; Brown, Jeffrey S
The Patient-Centered Outcomes Research Institute (PCORI) has launched PCORnet, a major initiative to support an effective, sustainable national research infrastructure that will advance the use of electronic health data in comparative effectiveness research (CER) and other types of research. In December 2013, PCORI's board of governors funded 11 clinical data research networks (CDRNs) and 18 patient-powered research networks (PPRNs) for a period of 18 months. CDRNs are based on the electronic health records and other electronic sources of very large populations receiving healthcare within integrated or networked delivery systems. PPRNs are built primarily by communities of motivated patients, forming partnerships with researchers. These patients intend to participate in clinical research, by generating questions, sharing data, volunteering for interventional trials, and interpreting and disseminating results. Rapidly building a new national resource to facilitate a large-scale, patient-centered CER is associated with a number of technical, regulatory, and organizational challenges, which are described here. PMID:24821743
Daily, Elizabeth B; Aquilante, Christina L
Cytochrome P450 (CYP) 2C8 is responsible for the oxidative metabolism of many clinically available drugs from a diverse number of drug classes (e.g., thiazolidinediones, meglitinides, NSAIDs, antimalarials and chemotherapeutic taxanes). The CYP2C8 enzyme is encoded by the CYP2C8 gene, and several common nonsynonymous polymorphisms (e.g., CYP2C8*2 and CYP2C8*3) exist in this gene. The CYP2C8*2 and *3 alleles have been associated in vitro with decreased metabolism of paclitaxel and arachidonic acid. Recently, the influence of CYP2C8 polymorphisms on substrate disposition in humans has been investigated in a number of clinical pharmacogenetic studies. Contrary to in vitro data, clinical data suggest that the CYP2C8*3 allele is associated with increased metabolism of the CYP2C8 substrates, rosiglitazone, pioglitazone and repaglinide. However, the CYP2C8*3 allele has not been associated with paclitaxel pharmacokinetics in most clinical studies. Furthermore, clinical data regarding the impact of the CYP2C8*3 allele on the disposition of NSAIDs are conflicting and no definitive conclusions can be made at this time. The purpose of this review is to highlight these clinical studies that have investigated the association between CYP2C8 polymorphisms and CYP2C8 substrate pharmacokinetics and/or pharmacodynamics in humans. In this review, CYP2C8 clinical pharmacogenetic data are provided by drug class, followed by a discussion of the future of CYP2C8 clinical pharmacogenetic research. PMID:19761371
Pearlman, Jay; Williams, Albert, III
The need for improved coordination in ocean observations is more urgent now given the issues of climate change, sustainable food sources and increased need for energy. Ocean researchers must work across disciplines to provide policy makers with clear and understandable assessments of the state of the ocean. With advances in technology, not only in observation, but also communication and computer science, we are in a new era where we can answer questions asked over the last 100 years at the time and space scales that are relevant. Programs like GLOBEC moved us forward but we are still challenged by the disciplinary divide. Interdisciplinary problem solving must be addressed not only by the exchange of data between the many sides, but through levels where questions require day-to-day collaboration. A National Science Foundation-funded Research Coordination Network (RCN) is addressing approaches for improving interdisciplinary research capabilities in the ocean sciences. During the last year, the RCN had a working group for Open Data led by John Orcutt, Peter Pissierssens and Albert Williams III. The teams has focused on three areas: 1. Data and Information formats and standards; 2. Data access models (including IPR, business models for open data, data policies,...); 3. Data publishing, data citation. There has been a significant trend toward free and open access to data in the last few years. In 2007, the US announced that Landsat data would be available at no charge. Float data from the US (NDBC), JCOMM and OceanSites offer web-based access. The IODE is developing its Ocean Data Portal giving immediate and free access to ocean data. However, from the aspect of long-term collaborations across communities, this global trend is less robust than might appear at the surface. While there are many standard data formats for data exchange, there is not yet widespread uniformity in their adoption. Use of standard data formats can be encouraged in several ways: sponsors of
On the basis of the interconnection of national networks of clinical research centres (CRCs) and clinical trials units (CTUs), the European Clinical Research Infrastructures Network (ECRIN) programme aims to develop an infrastructure allowing for bottom-up harmonisation of the support and training for, and practice of, clinical research, and to provide public sponsors for biotechnology small and medium-sized companies (SMEs) with support for translational research and multicentre clinical studies in Europe. This will be achieved through an application to the next FP6 'Integrated Infrastructure Initiatives' call. However, prior work is required to improve the reciprocal knowledge of partners in the ECRIN consortium and, as a first step, country-specific workshops will be organised by national networks in order to address the organisation of CRC/CTUs and national networks, and their interaction with the national environment of clinical research; this will enable in-depth discussion addressing the bottlenecks hampering transnational studies.
Hooper, R. P.; Kirschtl, D.
The hydrologic community has been discussing the concept of a network of observatories for the advancement of hydrologic science in areas of scaling processes, in testing generality of hypotheses, and in examining non-linear couplings between hydrologic, biotic, and human systems. The Consortium of Universities for the Advancement of Hydrologic Science, Inc. (CUAHSI) is exploring the formation of a virtual network of observatories, formed from existing field studies without regard to funding source. Such a network would encourage sharing of data, metadata, field methods, and data analysis techniques to enable multidisciplinary synthesis, meta-analysis, and scientific collaboration in hydrologic and environmental science and engineering. The virtual network would strive to provide both the data and the environmental context of the data through advanced cyberinfrastructure support. The foundation for this virtual network is Water Data Services that enable the publication of time-series data collected at fixed points using a services-oriented architecture. These publication services, developed in the CUAHSI Hydrologic Information Systems project, permit the discovery of data from both academic and government sources through a single portal. Additional services under consideration are publication of geospatial data sets, immersive environments based upon site digital elevation models, and a common web portal to member sites populated with structured data about the site (such as land use history and geologic setting) to permit understanding the environmental context of the data being shared.
Yang, Qin; Pan, Xiuqin; Wei, Daozhu; Wu, Ke
In order to establish an effective platform for individualized product development, the individualized product requirement expression forms were put forward. The diversity Semantic Network of product knowledge representation was researched based on the dualistic semantic network, and the product requirement framework model was established. Thereby the validity, reliability and consistency of the requirement expression process were ensured. Finally an example of customer requirement expression model about differential mechanism based on semantic network was described to satisfy with the individualized product design system.
Background Whether and how research training programs contribute to research network development is underexplored. The Fogarty International Center (FIC) has supported overseas research training programs for over two decades. FIC programs could provide an entry point in the development of research networks and collaborations. We examine whether FIC’s investment in research training contributed to the development of networks and collaborations in two countries with longstanding FIC investments – Uganda and Kenya – and the factors which facilitated this process. Methods As part of two case studies at Uganda’s Makerere University and Kenya’s University of Nairobi, we conducted 53 semi-structured in-depth interviews and nine focus group discussions. To expand on our case study findings, we conducted a focused bibliometric analysis on two purposively selected topic areas to examine scientific productivity and used online network illustration tools to examine the resulting network structures. Results FIC support made important contributions to network development. Respondents from both Uganda and Kenya confirmed that FIC programs consistently provided trainees with networking skills and exposure to research collaborations, primarily within the institutions implementing FIC programs. In both countries, networks struggled with inclusiveness, particularly in HIV/AIDS research. Ugandan respondents perceived their networks to be more cohesive than Kenyan respondents did. Network cohesiveness was positively correlated with the magnitude and longevity of FIC’s programs. Support from FIC grants to local and regional research network development and networking opportunities, such as conferences, was rare. Synergies between FIC programs and research grants helped to solidify and maintain research collaborations. Conclusions Networks developed where FIC’s programs focused on a particular institution, there was a critical mass of trainees with similar interests, and
Dozier, Ann M.; Martina, Camille A.; O’Dell, Nicole L.; Fogg, Thomas T.; Lurie, Stephen J.; Rubinstein, Eric P.; Pearson, Thomas A.
Clinical and translational research is a multidisciplinary, collaborative team process. To evaluate this process, we developed a method to document emerging research networks and collaborations in our medical center to describe their productivity and viability over time. Using an email survey, sent to 1,620 clinical and basic science full-and part-time faculty members, respondents identified their research collaborators. Initial analyses, using Pajek software, assessed the feasibility of using social network analysis (SNA) methods with these data. Nearly 400 respondents identified 1,594 collaborators across 28 medical center departments resulting in 309 networks with 5 or more collaborators. This low-burden approach yielded a rich dataset useful for evaluation using SNA to: a) assess networks at several levels of the organization, including intrapersonal (individuals), interpersonal (social), organizational/institutional leadership (tenure and promotion), and physical/environmental (spatial proximity) and b) link with other data to assess the evolution of these networks. PMID:24019209
Dozier, Ann M; Martina, Camille A; O'Dell, Nicole L; Fogg, Thomas T; Lurie, Stephen J; Rubinstein, Eric P; Pearson, Thomas A
Clinical and translational research is a multidisciplinary, collaborative team process. To evaluate this process, we developed a method to document emerging research networks and collaborations in our medical center to describe their productivity and viability over time. Using an e-mail survey, sent to 1,620 clinical and basic science full- and part-time faculty members, respondents identified their research collaborators. Initial analyses, using Pajek software, assessed the feasibility of using social network analysis (SNA) methods with these data. Nearly 400 respondents identified 1,594 collaborators across 28 medical center departments resulting in 309 networks with 5 or more collaborators. This low-burden approach yielded a rich data set useful for evaluation using SNA to: (a) assess networks at several levels of the organization, including intrapersonal (individuals), interpersonal (social), organizational/institutional leadership (tenure and promotion), and physical/environmental (spatial proximity) and (b) link with other data to assess the evolution of these networks.
Radi, Marjan; Dezfouli, Behnam; Abu Bakar, Kamalrulnizam; Lee, Malrey
A wireless sensor network is a large collection of sensor nodes with limited power supply and constrained computational capability. Due to the restricted communication range and high density of sensor nodes, packet forwarding in sensor networks is usually performed through multi-hop data transmission. Therefore, routing in wireless sensor networks has been considered an important field of research over the past decade. Nowadays, multipath routing approach is widely used in wireless sensor networks to improve network performance through efficient utilization of available network resources. Accordingly, the main aim of this survey is to present the concept of the multipath routing approach and its fundamental challenges, as well as the basic motivations for utilizing this technique in wireless sensor networks. In addition, we present a comprehensive taxonomy on the existing multipath routing protocols, which are especially designed for wireless sensor networks. We highlight the primary motivation behind the development of each protocol category and explain the operation of different protocols in detail, with emphasis on their advantages and disadvantages. Furthermore, this paper compares and summarizes the state-of-the-art multipath routing techniques from the network application point of view. Finally, we identify open issues for further research in the development of multipath routing protocols for wireless sensor networks.
Radi, Marjan; Dezfouli, Behnam; Bakar, Kamalrulnizam Abu; Lee, Malrey
A wireless sensor network is a large collection of sensor nodes with limited power supply and constrained computational capability. Due to the restricted communication range and high density of sensor nodes, packet forwarding in sensor networks is usually performed through multi-hop data transmission. Therefore, routing in wireless sensor networks has been considered an important field of research over the past decade. Nowadays, multipath routing approach is widely used in wireless sensor networks to improve network performance through efficient utilization of available network resources. Accordingly, the main aim of this survey is to present the concept of the multipath routing approach and its fundamental challenges, as well as the basic motivations for utilizing this technique in wireless sensor networks. In addition, we present a comprehensive taxonomy on the existing multipath routing protocols, which are especially designed for wireless sensor networks. We highlight the primary motivation behind the development of each protocol category and explain the operation of different protocols in detail, with emphasis on their advantages and disadvantages. Furthermore, this paper compares and summarizes the state-of-the-art multipath routing techniques from the network application point of view. Finally, we identify open issues for further research in the development of multipath routing protocols for wireless sensor networks. PMID:22368490
Learning networks are a critical element of ethos of the community action research approach taken by the Early Learning Initiative at the National College of Ireland, a community-based educational initiative in the Dublin Docklands. Key criteria for networking, whether at local, national or international level, are the individual's and…
Hodson, James, Comp.
This bibliography brings together sources, through August 1991, on the National Research and Education Network (NREN) and related topics, including computer networks, databases, information technology, library automation, microcomputers, and online systems. Where possible, a brief biographical note on the author is included, and most of the…
"The network" has achieved a form of "institutionalized utopianism" in the recent past and is posited as a neo-liberal solution to social scientific researchers and education practitioners learning with and from one another. This paper first outlines why the metaphor of the network is so persuasive. It goes on to problematize some of the key…
Learning networks are a critical element of ethos of the community action research approach taken by the Early Learning Initiative at the National College of Ireland, a community-based educational initiative in the Dublin Docklands. Key criteria for networking, whether at local, national or international level, are the individual's and…
García-González, Judit; Tansey, Katherine E; Hauser, Joanna; Henigsberg, Neven; Maier, Wolfgang; Mors, Ole; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Žagar, Tina; Czerski, Piotr M; Jerman, Borut; Buttenschøn, Henriette N; Schulze, Thomas G; Zobel, Astrid; Farmer, Anne; Aitchison, Katherine J; Craig, Ian; McGuffin, Peter; Giupponi, Michel; Perroud, Nader; Bondolfi, Guido; Evans, David; O'Donovan, Michael; Peters, Tim J; Wendland, Jens R; Lewis, Glyn; Kapur, Shitij; Perlis, Roy; Arolt, Volker; Domschke, Katharina; Breen, Gerome; Curtis, Charles; Sang-Hyuk, Lee; Kan, Carol; Newhouse, Stephen; Patel, Hamel; Baune, Bernhard T; Uher, Rudolf; Lewis, Cathryn M; Fabbri, Chiara
Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait. Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756). No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results. We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response. Copyright © 2017 Elsevier Inc. All rights reserved.
Abraham, Amanda J; Knudsen, Hannah K; Rothrauff, Tanja C; Roman, Paul M
Organizational participation in clinical research may lead to adoption of the intervention by treatment agencies, but it is not known whether research involvement enhances innovativeness beyond the specific interventions that are tested. The National Institute on Drug Abuse's Clinical Trials Network (CTN) is a platform for considering this research question. To date, the CTN has not conducted research on medications for alcohol use disorders (AUDs), so greater adoption of innovative AUD pharmacotherapies by CTN-affiliated programs would suggest an added value of research network participation. Using longitudinal data from a pooled sample of CTN and non-CTN publicly funded treatment programs, we investigate adoption of tablet naltrexone and acamprosate over a 2-year period. CTN-affiliated programs were more likely to have adopted tablet naltrexone and acamprosate at 24-month follow-up, net of the effects of a range of organizational characteristics. Research network participation may thus enhance organizational innovativeness to include interventions beyond the scope of the network.
Saskatchewan School Trustees Association, Regina.
School systems face the challenge of meeting high expectations with limited resources. Reductions in operating grants and increasing expenditures have exaggerated the problem. The Innovation Network was established by the Saskatchewan School Trustees Association in 1995 to help boards of education make the best use of available resources. This…
Despite the widespread popularity of social networking sites (SNSs) amongst children and young people in compulsory education, relatively little scholarly work has explored the fundamental issues at stake. This paper makes an original contribution to the field by locating the study of this online activity within the broader terrain of social…
Despite the widespread popularity of social networking sites (SNSs) amongst children and young people in compulsory education, relatively little scholarly work has explored the fundamental issues at stake. This paper makes an original contribution to the field by locating the study of this online activity within the broader terrain of social…
It is difficult for researchers of AD HOC network to conduct actual deployment during experimental stage as the network topology is changeable and location of nodes is unfixed. Thus simulation still remains the main research method of the network. Mobility model is an important component of AD HOC network simulation. It is used to describe the movement pattern of nodes in AD HOC network (including location and velocity, etc.) and decides the movement trail of nodes, playing as the abstraction of the movement modes of nodes. Therefore, mobility model which simulates node movement is an important foundation for simulation research. In AD HOC network research, mobility model shall reflect the movement law of nodes as truly as possible. In this paper, node generally refers to the wireless equipment people carry. The main research contents include how nodes avoid obstacles during movement process and the impacts of obstacles on the mutual relation among nodes, based on which a Node Self Avoiding Obstacle, i.e. NASO model is established in AD HOC network.
Aitchison, Katherine J; Malhotra, Anil K
The Ninth Annual Pharmacogenetics in Psychiatry meeting was held in New York City on 23-24 April 2010 with a series of panel presentations, as well as a debate on the commercialization of genetic testing and a poster reception. The following is a brief report of the meeting presentations.
Zhang, Jian-Ping; Aitchison, Katherine J; Malhotra, Anil K
The 12th Annual Pharmacogenetics in Psychiatry meeting was held in Hollywood, Florida, from 31 May to 1 June 2013, in conjunction with the NCDEU meeting. It included a series of oral presentations as well as a poster session. This report summarizes the presentations at the conference.
Robaey, Philippe; Krajinovic, Maja; Marcoux, Sophie; Moghrabi, Albert
Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in…
Florez, Jose C
In recent years, technological and analytical advances have led to an explosion in the discovery of genetic loci associated with type 2 diabetes. However, their ability to improve prediction of disease outcomes beyond standard clinical risk factors has been limited. On the other hand, genetic effects on drug response may be stronger than those commonly seen for disease incidence. Pharmacogenetic findings may aid in identifying new drug targets, elucidate pathophysiology, unravel disease heterogeneity, help prioritise specific genes in regions of genetic association, and contribute to personalised or precision treatment. In diabetes, precedent for the successful application of pharmacogenetic concepts exists in its monogenic subtypes, such as MODY or neonatal diabetes. Whether similar insights will emerge for the much more common entity of type 2 diabetes remains to be seen. As genetic approaches advance, the progressive deployment of candidate gene, large-scale genotyping and genome-wide association studies has begun to produce suggestive results that may transform clinical practice. However, many barriers to the translation of diabetes pharmacogenetic discoveries to the clinic still remain. This perspective offers a contemporary overview of the field with a focus on sulfonylureas and metformin, identifies the major uses of pharmacogenetics, and highlights potential limitations and future directions.
Robaey, Philippe; Krajinovic, Maja; Marcoux, Sophie; Moghrabi, Albert
Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in…
Duconge, Jorge; Cadilla, Carmen L.; Ruaño, Gualberto
Although the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes. CYP3A5*3 (0.245–0.867) showed the largest frequency in a US Hispanic population. A higher prevalence of CYP2C9*3, CYP2C19*4, and UGT2B7 IVS1+985 A>Gwas observed in US Hispanic vs. non-Hispanic populations. We found interethnic and intraethnic variability in frequencies of genetic polymorphisms for metabolizing enzymes, which highlights the need to define the ancestries of participants in pharmacogenetic studies. New approaches should be integrated in experimental designs to gain knowledge about the clinical relevance of the unique combination of genetic variants occurring in this admixed population. Ethnic subgroups in the US Hispanic population may harbor variants that might be part of multiple causative loci or in linkage-disequilibrium with functional variants. Pharmacogenetic studies in Hispanics should not be limited to ascertain commonly studied polymorphisms that were originally identified in their parental populations. The success of the Personalized Medicine paradigm will depend on recognizing genetic diversity between and within US Hispanics and the uniqueness of their genetic backgrounds. PMID:25431893
Last October, the 7th meeting of the Global Arthritis Research Network was held in Zurich, Switzerland. European and American experts who have made major recent contributions to molecular biology got together to provide insights into novel technologies and approaches useful for biomedical research, especially for research on arthritis and related conditions. PMID:21892971
This article focuses on the elaboration of institutional research practice, which is an important element of any research university. The study addresses three questions. First, how did institutional research arise, and what is its raison d'etre in a research university? Second, how can institutional research contribute to the improvement of the…
Bishop, Jeffrey R; Ellingrod, Vicki L
Pharmacogenetic research in the area of neuropsychiatric illnesses is rapidly evolving. Due to the complexity of the human brain, it is not surprising that our knowledge about the interaction between genetics and the treatment of these illnesses is very small. The Human Genome Project (HGP) has identified > 30,000 genes; several thousand of which have been found to occur in the brain or serve a role that enhances the brain's function. Much of the research in the post-HGP era is being driven by a desire to use genetics to predict which patients deviate from the norm in terms of drug response or side effects. By identifying these people, we will be able to direct clinical practice such that therapies for these disorders can be individualized. With this in mind, the following review is intended to cover a broad understanding of CNS pharmacogenetics with the goal of summarizing available literature on promising candidate gene targets, which may eventually help us predict clinical outcomes in patients taking medications commonly used to treat neuropsychiatric disorders.
McCormick, K; Langhorne, P; Graham, F E J; McFarlane, C
Research networks were introduced in the UK to facilitate and improve clinical research and stroke was seen as a priority topic for local research network development. The Scottish Stroke Research Network (SSRN) is one of 11 stroke research networks in the UK. In this article we review the progress of the Scottish Stroke Research Network in the three years since inception. Between 2006-2009 the number of active hospital research sites has increased from 10 to 22 expanding to involve 20 stroke research nurses. There was a corresponding 58% increase in recruitment of participants into stroke studies, from 376 in 2006/07 to 594 in 2008/09. The majority (17/20) of our current studies are interventional. Data from one of these, the CLOTs trial (Clots in Legs Or sTocking after Stroke), demonstrates that the annual recruitment in Scotland increased from a median of 94 (range 6-122) patients per year in the six years before the SSRN, to 140 (135-158) patients per year after SSRN involvement. We currently screen about 50% of Scottish stroke patients and approximately 5% of Scottish stroke patients are participating in research studies that we support. The SSRN has made good progress in the first three years. Increasing the recruitment of screened patients remains a challenge.
... Designing a Digital Future: Federally Funded Research and Development in Networking and Information Technology AGENCY: National Coordination Office (NCO) for the Networking and Information Technology Research... ``Designing a Digital Future: Federally Funded Research and Development in Networking and...
Chang, Chengwu; Huang, Huiming; Liu, Hongyang; Gao, Shenghua; Cheng, Liyu
Since the 21st century, Spatial laser communication has made a breakthrough development. Europe, the United States, Japan and other space powers have carried out the test of spatial laser communication technology on-orbit, and put forward a series of plans. In 2011, China made the first technology demonstration of satellite-ground laser communication carried by HY-2 satellite. Nowadays, in order to improve the transmission rate of spatial network, the topic of spatial laser communication network is becoming a research hotspot at home and abroad. This thesis, from the basic problem of spatial laser communication network to solve, analyzes the main difference between spatial network and ground network, which draws forth the key technology of spatial laser communication backbone network, and systematically introduces our research on aggregation, addressing, architecture of spatial network. From the perspective of technology development status and trends, the thesis proposes the development route of spatial laser communication network in stages. So as to provide reference about the development of spatial laser communication network in China.
Rose, Diana; Russo, Jasna; Wykes, Til
This study is the first to examine the understandings that participants have of the consent process in a pharmacogenetic trial of anti-depressant medication. This was a qualitative cross sectional study. There were 76 participants residing in London, Mannheim, Arhuus and Poznan. Only one quarter of participants (none in Poznan) could articulate the concept of pharmacogenetics. Heritability and testing medication were also given as the purpose of the trial. Most participants had not appreciated harms that could derive from the trial. Even when shown the consent sheet, participants were confused about DNA profiling. There was evidence that participants appreciated weekly contact with researchers. Most said they would participate in a trial again but would like choice over the intervention they were assigned to. Participants in this study showed a poor level of informed consent. Although this is not the first time this argument has been made, it is in the case of a pharmacogenetic trial. Further work should investigate the associations between extraneous factors such as information and social support on beneficial or untoward outcomes of antidepressant treatment.
traffic on the network, either by using mathematical formulas or by replaying packet streams. As a result, simulators depend deeply on the assumptions...Summary of the most important results We obtained a powerful machine, which has 768 cores and 1.25 TB memory . RBG has been implemented on the machine...is configured with 1GB memory , 10 GB disk space, and one 100M Ethernet interface. The server nodes include web servers, database servers, email
Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H
To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.
Gupta, Pooja D.
The value of health care can be increased tremendously through individualized medicine. With the promise of individualized medicine, healthcare professionals will be able to better predict disease risk, prevent development of disease and manage treatments more efficiently thereby allowing people to be healthier and active longer. The developments in the area of pharmacogenetics/pharmacogenomics can help the physicians achieve the target of personalized medicine. Personalized medicine will come to mean not just the right drug for the right individual, but the right drug for the specific disease affecting a specific individual. The use of personalized medicine will make clinical trials more efficient by lowering the costs that would arise due to adverse drug effects and prescription of drugs that have been proven ineffective in certain genotypes. The genotypic experiments have laid valuable insights into genetic underpinnings of diseases. However it is being realized that identification of sub-groups within normal controls corresponding to contrasting disease susceptibility could lead to more effective discovery of predictive markers for diseases. However there are no modern methods available to look at the inter-individual differences within ethnically matched healthy populations. Ayurveda, an exquisitely elaborate system of predictive medicine which has been practiced for over 3500 years in India, can help in bridging this gap. In contrast to the contemporary system of medicine, the therapeutic regimen in Ayurveda is implicated on tridoshas and prakriti. According to this system, every individual is born with his or her own basic constitution, which to a great extent regulates inter-individual variability in susceptibility to diseases and response to external environment, diet and drugs. Thus the researchers in India have demonstrated that integration of this stratified approach of Ayurveda into genomics i.e. Ayurgenomics could complement personalized medicine
Gupta, Pooja D
The value of health care can be increased tremendously through individualized medicine. With the promise of individualized medicine, healthcare professionals will be able to better predict disease risk, prevent development of disease and manage treatments more efficiently thereby allowing people to be healthier and active longer. The developments in the area of pharmacogenetics/pharmacogenomics can help the physicians achieve the target of personalized medicine. Personalized medicine will come to mean not just the right drug for the right individual, but the right drug for the specific disease affecting a specific individual. The use of personalized medicine will make clinical trials more efficient by lowering the costs that would arise due to adverse drug effects and prescription of drugs that have been proven ineffective in certain genotypes. The genotypic experiments have laid valuable insights into genetic underpinnings of diseases. However it is being realized that identification of sub-groups within normal controls corresponding to contrasting disease susceptibility could lead to more effective discovery of predictive markers for diseases. However there are no modern methods available to look at the inter-individual differences within ethnically matched healthy populations. Ayurveda, an exquisitely elaborate system of predictive medicine which has been practiced for over 3500 years in India, can help in bridging this gap. In contrast to the contemporary system of medicine, the therapeutic regimen in Ayurveda is implicated on tridoshas and prakriti. According to this system, every individual is born with his or her own basic constitution, which to a great extent regulates inter-individual variability in susceptibility to diseases and response to external environment, diet and drugs. Thus the researchers in India have demonstrated that integration of this stratified approach of Ayurveda into genomics i.e. Ayurgenomics could complement personalized medicine.
Weber, Griffin M; Barnett, William; Conlon, Mike; Eichmann, David; Kibbe, Warren; Falk-Krzesinski, Holly; Halaas, Michael; Johnson, Layne; Meeks, Eric; Mitchell, Donald; Schleyer, Titus; Stallings, Sarah; Warden, Michael; Kahlon, Maninder
Research-networking tools use data-mining and social networking to enable expertise discovery, matchmaking and collaboration, which are important facets of team science and translational research. Several commercial and academic platforms have been built, and many institutions have deployed these products to help their investigators find local collaborators. Recent studies, though, have shown the growing importance of multiuniversity teams in science. Unfortunately, the lack of a standard data-exchange model and resistance of universities to share information about their faculty have presented barriers to forming an institutionally supported national network. This case report describes an initiative, which, in only 6 months, achieved interoperability among seven major research-networking products at 28 universities by taking an approach that focused on addressing institutional concerns and encouraging their participation. With this necessary groundwork in place, the second phase of this effort can begin, which will expand the network's functionality and focus on the end users.
Barnett, William; Conlon, Mike; Eichmann, David; Kibbe, Warren; Falk-Krzesinski, Holly; Halaas, Michael; Johnson, Layne; Meeks, Eric; Mitchell, Donald; Schleyer, Titus; Stallings, Sarah; Warden, Michael; Kahlon, Maninder
Research-networking tools use data-mining and social networking to enable expertise discovery, matchmaking and collaboration, which are important facets of team science and translational research. Several commercial and academic platforms have been built, and many institutions have deployed these products to help their investigators find local collaborators. Recent studies, though, have shown the growing importance of multiuniversity teams in science. Unfortunately, the lack of a standard data-exchange model and resistance of universities to share information about their faculty have presented barriers to forming an institutionally supported national network. This case report describes an initiative, which, in only 6 months, achieved interoperability among seven major research-networking products at 28 universities by taking an approach that focused on addressing institutional concerns and encouraging their participation. With this necessary groundwork in place, the second phase of this effort can begin, which will expand the network's functionality and focus on the end users. PMID:22037890
Lachmann, Ulrike; Villringer, Arno
In 1999 the German Ministry of Education and Research initiated a funding initiative for competence networks in health research in order to improve research and health care for major diseases with high morbidity and relevance to public health. All major players in a given field were invited to cooperate. The aims were to improve horizontal as well as vertical networking in order to improve research quality and the transfer of new results into general clinical practice. Another aim was to establish sustainable structures for lasting cooperation. After a highly competitive application round, the Competence Network Stroke was among the very first to be funded. The incidence of stroke in Germany is about 250,000 new patients per year, it is the leading cause of adult impairment and its societal impact is dramatic.This article describes how the Competence Network Stroke managed to meet the above-mentioned goals and how cooperation among stroke researchers and caregivers in Germany has improved. Furthermore it provides examples of researcher achievements in the network, which have advanced research and benefited patients.
Vacca, Raffaele; Kennelly Okraku, Therese; McCarty, Christopher
A growing body of evidence shows that collaborative teams and communities tend to produce the highest-impact scientific work. This paper proposes a new method to (1) Identify collaborative communities in longitudinal scientific networks, and (2) Evaluate the impact of specific research institutes, services or policies on the interdisciplinary collaboration between these communities. First, we apply community-detection algorithms to cross-sectional scientific collaboration networks and analyze different types of co-membership in the resulting subgroups over time. This analysis summarizes large amounts of longitudinal network data to extract sets of research communities whose members have consistently collaborated or shared collaborators over time. Second, we construct networks of cross-community interactions and estimate Exponential Random Graph Models to predict the formation of interdisciplinary collaborations between different communities. The method is applied to longitudinal data on publication and grant collaborations at the University of Florida. Results show that similar institutional affiliation, spatial proximity, transitivity effects, and use of the same research services predict higher degree of interdisciplinary collaboration between research communities. Our application also illustrates how the identification of research communities in longitudinal data and the analysis of cross-community network formation can be used to measure the growth of interdisciplinary team science at a research university, and to evaluate its association with research policies, services or institutes. PMID:28797047
Nebert, Daniel W.; Zhang, Ge; Vesell, Elliot S.
A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies—have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that “personalized medicine is almost here” or that “individualized drug therapy will soon be a reality.” As summarized herein, numerous reasons exist to show that an “unequivocal genotype” or even an “unequivocal phenotype” is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone. PMID:18464043
Nebert, Daniel W; Zhang, Ge; Vesell, Elliot S
A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies - have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.
Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina
Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.
De Mattia, Elena; Dreussi, Eva; Cecchin, Erika; Toffoli, Giuseppe
In the last decade, genetic variations in ABC/SLC transporters and phase I/II enzymes have raised pharmacogenetic markers as being predictive to the attention of researchers in the field of personalized medicine in oncology. However, it is becoming evident that the sequence variations in these genes cannot address by themselves the sharp interindividual variability in drug effects. Recently, nuclear receptors (NRs), including pregnane X receptor, constitutive androstane receptor, retinoid X receptor, farnesoid X receptor, liver X receptor, vitamin D receptor, peroxisome proliferator-activated receptors and HNF4A, have demonstrated key roles in regulating transporter and metabolic gene expression in response to xeno/endobiotics, as well as antineoplastic drugs. These findings attracted interest to the genetics of the NRs for their possible role in influencing the metabolism and pharmacological profiles of chemotherapeutics. In this review, we aim to summarize the most recent findings in the innovative field of NR pharmacogenetics and findings in how they could integrate with more traditional markers in order to improve drug treatment personalization.
Fabbri, Chiara; Serretti, Alessandro
The pharmacogenetics of antidepressants has been not only a challenging but also frustrating research field since its birth in the 1990s. Indeed, great expectations followed the first evidence of familiar aggregation of antidepressant response. Despite the progress from candidate gene studies to genome-wide association studies (GWAS), results fell out the expectations and they were often inconsistent. Anyway, the cumulative evidence supports the involvement of some genes and molecular pathways in antidepressant efficacy. The best single genes are SLC6A4, HTR2A, BDNF, GNB3, FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19). Molecular pathways involved in inflammation and neuroplasticity show the greatest support. The first studies evaluating benefits of genotype-guided antidepressant treatments provided encouraging results and confirmed the relevance of SLC6A4, HTR2A, ABCB1, and cytochrome P450 genes. Further progress in genotyping and data analysis would allow to move forward and complete the understanding of antidepressant pharmacogenetics and its translation into clinical applications.
Agosta, Elisa; Lazzeri, Stefano; Orlandi, Paola; Figus, Michele; Fioravanti, Anna; Di Desidero, Teresa; Sartini, Maria Sole; Nardi, Marco; Danesi, Romano; Bocci, Guido
Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.
Jett, David A.; Yeung, David T.
The National Institutes of Health has developed a comprehensive research program that includes research centers of excellence, individual research projects, small business projects, contracts, and interagency agreements to conduct basic, translational, and clinical research aimed at the discovery and/or identification of better medical countermeasures against chemical threat agents. Chemical threats include chemical warfare agents, toxic industrial and agricultural chemicals, and toxins and other chemicals that could be used intentionally as an act of terror or by large-scale accidents or natural disasters. The overarching goal of this research program is to enhance our medical response capabilities during an emergency. The program is named Countermeasures Against Chemical Threats (CounterACT). It supports translational research, applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of mortality and morbidity caused by chemical threat agents. The categories of research supported under this program include creation and development of screening assays and animal models for therapy development, identification of candidate therapeutics, obtaining preliminary proof-of-principle data on the efficacy of candidate therapeutics, advanced efficacy and preclinical safety studies with appropriate animal models using Good Laboratory Practices (GLP), and clinical studies, including clinical trials with new drugs. Special consideration is given to research relevant to people who are particularly vulnerable, including the young, the elderly, and individuals with pre-existing medical conditions. PMID:20601628
Galván-Plata, María Eugenia; Almeida-Gutiérrez, Eduardo; Salamanca-Gómez, Fabio Abdel
The Instituto Mexicano del Seguro Social (IMSS) through the Coordinación de Investigación en Salud (Health Research Council) has promoted a strong link between the generation of scientific knowledge and the clinical care through the program Redes Institucionales de Investigación (Institutional Research Network Program), whose main aim is to promote and generate collaborative research between clinical, basic, epidemiologic, educational, economic and health services researchers, seeking direct benefits for patients, as well as to generate a positive impact on institutional processes. All of these research lines have focused on high-priority health issues in Mexico. The IMSS internal structure, as well as the sufficient health services coverage, allows the integration of researchers at the three levels of health care into these networks. A few years after their creation, these networks have already generated significant results, and these are currently applied in the institutional regulations in diseases that represent a high burden to health care. Two examples are the National Health Care Program for Patients with Acute Myocardial Infarction "Código Infarto", and the Early Detection Program on Chronic Kidney Disease; another result is the generation of multiple scientific publications, and the promotion of training of human resources in research from the same members of our Research Networks. There is no doubt that the Coordinación de Investigación en Salud advances steadily implementing the translational research, which will keep being fruitful to the benefit of our patients, and of our own institution.
Society for Participatory Research in Asia, New Delhi (India).
Participatory research is an approach that calls for a democratic interaction between the researcher and those among whom the research is conducted. While this approach has been implemented with both individuals and groups in a wide variety of settings such as geographic communities, workplace situations, adult learning groups, community issue…
Society for Participatory Research in Asia, New Delhi (India).
Participatory research is an approach that calls for a democratic interaction between the researcher and those among whom the research is conducted. While this approach has been implemented with both individuals and groups in a wide variety of settings such as geographic communities, workplace situations, adult learning groups, community issue…
Hanauer, David I.; Hatfull, Graham
The aim of this paper is to propose, present, and validate a simple survey instrument to measure student conversational networking. The tool consists of five items that cover personal and professional social networks, and its basic principle is the self-reporting of degrees of conversation, with a range of specific discussion partners. The networking instrument was validated in three studies. The basic psychometric characteristics of the scales were established by conducting a factor analysis and evaluating internal consistency using Cronbach’s alpha. The second study used a known-groups comparison and involved comparing outcomes for networking scales between two different undergraduate laboratory courses (one involving a specific effort to enhance networking). The final study looked at potential relationships between specific networking items and the established psychosocial variable of project ownership through a series of binary logistic regressions. Overall, the data from the three studies indicate that the networking scales have high internal consistency (α = 0.88), consist of a unitary dimension, can significantly differentiate between research experiences with low and high networking designs, and are related to project ownership scales. The ramifications of the networking instrument for student retention, the enhancement of public scientific literacy, and the differentiation of laboratory courses are discussed. PMID:26538387
Mold, James W
This seventh annual practice-based research theme issue of the Journal of the American Board of Family Medicine highlights primary care research conducted in practice-based research networks (PBRNs). The issue includes discussion of (1) theoretical and methodological research, (2) health care research (studies addressing primary care processes), (3) clinical research (studies addressing the impact of primary care on patients), and (4) health systems research (studies of health system issues impacting primary care including the quality improvement process). We had a noticeable increase in submissions from PBRN collaborations, that is, studies that involved multiple networks. As PBRNs cooperate to recruit larger and more diverse patient samples, greater generalizability and applicability of findings lead to improved primary care processes.
Bian, Jiang; Xie, Mengjun; Topaloglu, Umit; Hudson, Teresa; Eswaran, Hari; Hogan, William
The popularity of social networks has triggered a number of research efforts on network analyses of research collaborations in the Clinical and Translational Science Award (CTSA) community. Those studies mainly focus on the general understanding of collaboration networks by measuring common network metrics. More fundamental questions about collaborations still remain unanswered such as recognizing "influential" nodes and identifying potential new collaborations that are most rewarding. We analyzed biomedical research collaboration networks (RCNs) constructed from a dataset of research grants collected at a CTSA institution (i.e., University of Arkansas for Medical Sciences (UAMS)) in a comprehensive and systematic manner. First, our analysis covers the full spectrum of a RCN study: from network modeling to network characteristics measurement, from key nodes recognition to potential links (collaborations) suggestion. Second, our analysis employs non-conventional model and techniques including a weighted network model for representing collaboration strength, rank aggregation for detecting important nodes, and Random Walk with Restart (RWR) for suggesting new research collaborations. By applying our models and techniques to RCNs at UAMS prior to and after the CTSA, we have gained valuable insights that not only reveal the temporal evolution of the network dynamics but also assess the effectiveness of the CTSA and its impact on a research institution. We find that collaboration networks at UAMS are not scale-free but small-world. Quantitative measures have been obtained to evident that the RCNs at UAMS are moving towards favoring multidisciplinary research. Moreover, our link prediction model creates the basis of collaboration recommendations with an impressive accuracy (AUC: 0.990, MAP@3: 1.48 and MAP@5: 1.522). Last but not least, an open-source visual analytical tool for RCNs is being developed and released through Github. Through this study, we have developed a set
Bian, Jiang; Xie, Mengjun; Topaloglu, Umit; Hudson, Teresa; Eswaran, Hari; Hogan, William
BACKGROUND The popularity of social networks has triggered a number of research efforts on network analyses of research collaborations in the Clinical and Translational Science Award (CTSA) community. Those studies mainly focus on the general understanding of collaboration networks by measuring common network metrics. More fundamental questions about collaborations still remain unanswered such as recognizing “influential” nodes and identifying potential new collaborations that are most rewarding. METHODS We analyzed biomedical research collaboration networks (RCNs) constructed from a dataset of research grants collected at a CTSA institution (i.e. University of Arkansas for Medical Sciences (UAMS)) in a comprehensive and systematic manner. First, our analysis covers the full spectrum of a RCN study: from network modeling to network characteristics measurement, from key nodes recognition to potential links (collaborations) suggestion. Second, our analysis employs non-conventional model and techniques including a weighted network model for representing collaboration strength, rank aggregation for detecting important nodes, and Random Walk with Restart (RWR) for suggesting new research collaborations. RESULTS By applying our models and techniques to RCNs at UAMS prior to and after the CTSA, we have gained valuable insights that not only reveal the temporal evolution of the network dynamics but also assess the effectiveness of the CTSA and its impact on a research institution. We find that collaboration networks at UAMS are not scale-free but small-world. Quantitative measures have been obtained to evident that the RCNs at UAMS are moving towards favoring multidisciplinary research. Moreover, our link prediction model creates the basis of collaboration recommendations with an impressive accuracy (AUC: 0.990, MAP@3: 1.48 and MAP@5: 1.522). Last but not least, an open-source visual analytical tool for RCNs is being developed and released through Github. CONCLUSIONS
Roberts, J.; Calhoun, V.
The scientific and technological programs of the Mind Research Network (MRN), reflect DOE missions in basic science and associated instrumentation, computational modeling, and experimental techniques. MRN's technical goals over the course of this project have been to develop and apply integrated, multi-modality functional imaging techniques derived from a decade of DOE-support research and technology development.
Guerrero-Rascado, Juan Luis; Landulfo, Eduardo; Antuña, Juan Carlos; de Melo Jorge Barbosa, Henrique; Barja, Boris; Bastidas, Álvaro Efrain; Bedoya, Andrés Esteban; da Costa, Renata Facundes; Estevan, René; Forno, Ricardo; Gouveia, Diego Alvés; Jiménez, Cristofer; Larroza, Eliane Gonçalves; da Silva Lopes, Fábio Juliano; Montilla-Rosero, Elena; de Arruda Moreira, Gregori; Nakaema, Walker Morinobu; Nisperuza, Daniel; Alegria, Dairo; Múnera, Mauricio; Otero, Lidia; Papandrea, Sebastián; Pallota, Juan Vicente; Pawelko, Ezequiel; Quel, Eduardo Jaime; Ristori, Pablo; Rodrigues, Patricia Ferrini; Salvador, Jacobo; Sánchez, Maria Fernanda; Silva, Antonieta
LALINET (Latin American Lidar Network), previously known as ALINE, is the first fully operative lidar network for aerosol research in South America, probing the atmosphere on regular basis since September 2013. The general purpose of this network is to attempt to fill the gap in the knowledge on aerosol vertical distribution over South America and its direct and indirect impact on weather and climate by the establishment of a vertically-resolved dataset of aerosol properties. Similarly to other lidar research networks, most of the LALINET instruments are not commercially produced and, consequently, configurations, capabilities and derived-products can be remarkably different among stations. It is a fact that such un-biased 4D dataset calls for a strict standardization from the instrumental and data processing point of view. This study has been envisaged to investigate the ongoing network configurations with the aim of highlighting the instrumental strengths and weaknesses of LALINET.
Fernández, M Isabel; Wheeler, Darrell P; Alfonso, Sarah V
Responding to the demands of the HIV/AIDS epidemic necessitates a diverse scientific and clinical workforce trained in applying interdisciplinary research approaches to address the epidemic domestically and internationally. Ensuring diversity in our workforce requires concerted efforts. Yet, the majority of graduate and post-graduate programs are ill-equipped to provide this type of training. Research networks, the HPTN, HVTN, CFAR and ATN, are uniquely positioned to implement interdisciplinary mentoring programs and all four have done so. We describe these programs, the nuts and bolts of program implementation and efforts to recruit and retain diversity scholars. We outline some inherent challenges such as competing demands for network resources or tension in aligning scholars' research agenda with that of the networks. We argue that the benefits to be gained from continuing these programs far outweigh their costs and that these programs are an essential component of a comprehensive strategy for developing the future HIV research workforce.
Wang, Niannian; Zhang, Li; Liu, Guozhong
Recently, exploring the cognitive functions of the brain by establishing a network model to understand the working mechanism of the brain has become a popular research topic in the field of neuroscience. In this study, electroencephalography (EEG) was used to collect data from subjects given four different mathematical cognitive tasks: recite numbers clockwise and counter-clockwise, and letters clockwise and counter-clockwise to build a complex brain function network (BFN). By studying the connectivity features and parameters of those brain functional networks, it was found that the average clustering coefficient is much larger than its corresponding random network and the average shortest path length is similar to the corresponding random networks, which clearly shows the characteristics of the small-world network. The brain regions stimulated during the experiment are consistent with traditional cognitive science regarding learning, memory, comprehension, and other rational judgment results. The new method of complex networking involves studying the mathematical cognitive process of reciting, providing an effective research foundation for exploring the relationship between brain cognition and human learning skills and memory. This could help detect memory deficits early in young and mentally handicapped children, and help scientists understand the causes of cognitive brain disorders.
Public concern about wind erosion in the United States is high. This concern has arisen as a consequence of changing and intensifying land use pressures which can lead to increased soil loss and dust emission. However, there is relatively little research to support improved management. While much at...
Much has been written about the use of information and communication technology (ICT) in distance learning environments. A quick Google search turns up as many as 178,000 links to the term. ICT has been less used and discussed as a means of communication between research student and supervisor--particularly where this is the major means of student…
Robinson, Tracy Elizabeth; Rankin, Nicole; Janssen, Anna; Mcgregor, Deborah; Grieve, Stuart; Shaw, Timothy
Collaborative research networks are often touted as a solution for enhancing the translation of knowledge, but questions remain about how to evaluate their impact on health service delivery. This pragmatic scoping study explored the enabling factors for developing and supporting a collaborative imaging network in a metropolitan university in Australia. An advisory group was established to provide governance and to identify key informants and participants. Focus group discussions (n = 2) and semi-structured interviews (n = 22) were facilitated with representatives from a broad range of disciplines. In addition, a survey, a review of relevant websites (n = 15) and a broad review of the literature were undertaken to elicit information on collaborative research networks and perceived needs and factors that would support their involvement in a multi-disciplinary collaborative research network. Findings were de-identified and broad themes were identified. Participants identified human factors as having priority for developing and sustaining a collaborative research network. In particular, leadership, a shared vision and a communication plan that includes social media were identified as crucial for sustaining an imaging network in health research. It is important to develop metrics that map relationships between network members and the role that communication tools can contribute to this process. This study confirms that human factors remain significant across a range of collaborative endeavours. The use of focus group discussions, interviews, and literature and website reviews means we can now strongly recommend the primacy of human factors. More work is needed to identify how the network operates and what specific indicators or metrics help build the capacity of clinicians and scientists to participate in translational research.
We will demonstrate operation of one or more meter-class telescopes devoted to student initiated astronomical research projects. For multiple decades astronomers have promised each other the development of global networks of telescopes. For the last decade, without ever fulfilling the initial promise, we have upped the ante and promised global networks of robotic telescopes. Sometimes the network is to be composed of 20- to 40-cm aperture telescopes; other times the network will include meter-class telescopes. Sometimes the network is exclusive to a select, small group of users; other times the dream is open to any interested parties. Western Kentucky University, the Hands-On Universe project, and NASA's Kepler mission have achieved the first components of a network of telescopes established for educational programs. We will discuss the process used by teachers and students to make use of a substantial fraction of the network's observing time, and to access most of the archived data. Examples of student projects will be shared, along with immediate plans for expanding the network.
Glickman, Seth W; Kit Delgado, M; Hirshon, Jon Mark; Hollander, Judd E; Iwashyna, Theodore J; Jacobs, Alice K; Kilaru, Austin S; Lorch, Scott A; Mutter, Ryan L; Myers, Sage R; Owens, Pamela L; Phelan, Michael P; Pines, Jesse M; Seymour, Christopher W; Ewen Wang, N; Branas, Charles C
The demands on emergency services have grown relentlessly, and the Institute of Medicine (IOM) has asserted the need for "regionalized, coordinated, and accountable emergency care systems throughout the country." There are large gaps in the evidence base needed to fix the problem of how emergency care is organized and delivered, and science is urgently needed to define and measure success in the emerging network of emergency care. In 2010, Academic Emergency Medicine convened a consensus conference entitled "Beyond Regionalization: Integrated Networks of Emergency Care." This article is a product of the conference breakout session on "Defining and Measuring Successful Networks"; it explores the concept of integrated emergency care delivery and prioritizes a research agenda for how to best define and measure successful networks of emergency care. The authors discuss five key areas: 1) the fundamental metrics that are needed to measure networks across time-sensitive and non-time-sensitive conditions; 2) how networks can be scalable and nimble and can be creative in terms of best practices; 3) the potential unintended consequences of networks of emergency care; 4) the development of large-scale, yet feasible, network data systems; and 5) the linkage of data systems across the disease course. These knowledge gaps must be filled to improve the quality and efficiency of emergency care and to fulfill the IOM's vision of regionalized, coordinated, and accountable emergency care systems. 2010 by the Society for Academic Emergency Medicine.
Kratochvil, D.; Sood, D.; Verostko, A.
During the last decade, NASA LeRC's Communication Program has conducted a series of telecommunications forecasting studies to project trends and requirements and to identify critical telecommunications technologies that must be developed to meet future requirements. The Government Networks Division of Contel Federal Systems has assisted NASA in these studies, and the current study builds upon these earlier efforts. The current major thrust of the NASA Communications Program is aimed at developing the high risk, advanced, communications satellite and terminal technologies required to significantly increase the capacity of future communications systems. Also, major new technological, economic, and social-political events and trends are now shaping the communications industry of the future. Therefore, a re-examination of future telecommunications needs and requirements is necessary to enable NASA to make management decisions in its Communications Program and to ensure the proper technologies and systems are addressed. This study, through a series of Task Orders, is helping NASA define the likely communication service needs and requirements of the future and thereby ensuring that the most appropriate technology developments are pursued.
... FOUNDATION Networking and Information Technology Research and Development (NITRD) Program: Draft NITRD 2010 Strategic Plan--URL Correction AGENCY: The National Coordination Office (NCO) for Networking and Information... Coordination Office for Networking and Information Technology Research and Development (NITRD) requests...
Mays, Glen P.; Hogg, Rachel A.
BACKGROUND Delivery system research to identify how best to organize, finance, and implement health improvement strategies has focused heavily on clinical practice settings, with relatively little attention paid to public health settings – where research is made more difficult by wide heterogeneity in settings and limited sources of existing data and measures. This study examines the approaches used by Public Health Practice-Based Research Networks (PBRNs) to expand delivery system research and evidence-based practice in public health settings. METHODS PBRN research networks employ quasi-experimental research designs, natural experiments, and mixed-method analytic techniques to evaluate how community partnerships, economic shocks, and policy changes impact delivery processes in public health settings. Additionally, network analysis methods are used to assess patterns of interaction between practitioners and researchers within PBRNs to produce and apply research findings. RESULTS Findings from individual PBRN studies elucidate the roles of information exchange, community resources, and leadership and decision-making structures in shaping implementation outcomes in public health delivery. Network analysis of PBRNs reveals broad engagement of both practitioners and researchers in scientific inquiry, with practitioners in the periphery of these networks reporting particularly large benefits from research participation. CONCLUSIONS Public Health PBRNs provide effective mechanisms for implementing delivery system research, engaging practitioners in the process, and accelerating the translation and application of research findings into public health settings. PMID:23023272
Hudson, Peter; Street, Annette; Graham, Suzanne; Aranda, Sanchia; O'Connor, Margaret; Thomas, Kristina; Jackson, Kate; Spruyt, Odette; Ugalde, Anna; Philip, Jennifer
The difficulties in conducting palliative care research have been widely acknowledged. In order to generate the evidence needed to underpin palliative care provision, collaborative research is considered essential. Prior to formalizing the development of a research network for the state of Victoria, Australia, a preliminary study was undertaken to ascertain interest and recommendations for the design of such a collaboration. Three data-collection strategies were used: a cross-sectional questionnaire, interviews, and workshops. The questionnaire was completed by multidisciplinary palliative care specialists from across the state (n = 61); interviews were conducted with senior clinicians and academics (n = 21) followed by two stakeholder workshops (n = 29). The questionnaire was constructed specifically for this study, measuring involvement of and perceptions of palliative care research. Both the interview and the questionnaire data demonstrated strong support for a palliative care research network and aided in establishing a research agenda. The stakeholder workshops assisted with strategies for the formation of the Palliative Care Research Network Victoria (PCRNV) and guided the development of the mission and strategic plan. The research and efforts to date to establish the PCRNV are encouraging and provide optimism for the evolution of palliative care research in Australia. The international implications are highlighted.
Functionality and architecture of the NSRL Telemetry Warehouse are also described as well as the web interface, data structure, security aspects, and...Experiment Controller 6 4.5 Telemetry Sensors 7 4.6 Custom Data Processing Nodes 7 5. Web Interface 8 6. Data Structure 8 6.1 Measurements 8...telemetry in comma-separated value (CSV) format from the web interface or via custom applications developed by researchers using the client application
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Agriculture faces tremendous challenges in meeting multiple societal goals, including a safe and plentiful food supply; climate change adaptation and mitigation; supplying sources of bioenergy; improving water, air, and soil quality; and maintaining biodiversity. The Long Term Agroecosystem Research...
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.
Böhm, Ruwen; Cascorbi, Ingolf
Adverse drug reactions adverse drug reaction (ADR) occur in approximately 17% of patients. Avoiding ADR is thus mandatory from both an ethical and an economic point of view. Whereas, pharmacogenetics changes of the pharmacokinetics may contribute to the explanation of some type A reactions, strong relationships of genetic markers has also been shown for drug hypersensitivity belonging to type B reactions. We present the classifications of ADR, discuss genetic influences and focus on delayed-onset hypersensitivity reactions, i.e., drug-induced liver injury, drug-induced agranulocytosis, and severe cutaneous ADR. A guidance how to read and interpret the contingency table is provided as well as an algorithm whether and how a test for a pharmacogenetic biomarker should be conducted. PMID:27818635
Hosford, David A; Lai, Eric H; Riley, John H; Xu, Chun-Fang; Danoff, Theodore M; Roses, Allen D
Identification of reliable markers to predict drug-related adverse events (DRAEs) is an important goal of the pharmaceutical industry and others within the healthcare community. We have used genetic polymorphisms, including the most frequent source of variation (single nucleotide polymorphisms, SNPs) in the human genome, in pharmacogenetic approaches designed to predict DRAEs. Three studies exemplify the principles of using polymorphisms to identify associations in progressively larger genomic regions: polymorphic repeats within the UDP-glucuronysltransferase I (UGT1A1) gene in patients experiencing hyperbilirubinemia after administration of tranilast, an experimental drug to prevent re-stenosis following coronary revascularization; high linkage disequilibrium within the Apolipoprotein E (ApoE) gene in patients with Alzheimer Disease (AD); and the polymorphic variant HLA-B57 in patients with hypersensitivity reaction after administration of abacavir, a nucleoside reverse transcriptase inhibitor for the treatment of HIV. Together, these studies demonstrate in a stepwise manner the feasibility of using pharmacogenetic approaches to predict DRAEs.
Sugino, Shigekazu; Janicki, Piotr K
Chemotherapy-induced nausea and vomiting (CINV) is associated with distressing adverse effects observed in patients during cytotoxic chemotherapy. One of the potential factors explaining suboptimal response to currently used antiemetics is variability in genes encoding enzymes and proteins that play a role in the action of antiemetic drugs. Pharmacogenomics studies of CINV are sparse and focus mainly on polymorphisms associated with serotonin receptor, drug metabolism and drug transport. Currently, the role of pharmacogenetics in mechanisms of CINV has not been fully unraveled, and it is premature to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice. More uniform studies, with genetic profiles and biomarkers relevant for the proposed target and transporter mechanisms, are needed.
Ampuero, Javier; Romero-Gómez, Manuel
Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.
Pharmacogenetics takes into account the individual variability of the genome and its relationships with drug activity. Numerous gene polymorphisms occurring at the level of drug metabolising enzymes, drug transporters or drug targets have been identified; they may be responsible for an alteration of the phenotype, and of individual changes in drug efficacy and/or toxicity. Pharmacogenomics takes into account the genetic alterations present in tumours and their role in drug activity. It may be possible to establish correlations between the activity of a drug and the level of expression of tumour genes, and thus select the most appropriate drugs to prescribe for the treatment of individual tumours. Pharmacogenetics and pharmacogenomics are acting synergistically for the personalisation of treatments, on the basis of the constitutive singularity of patients and of the molecular characteristics of tumours.
Baker-Doyle, Kira J.
Social network research on teachers and schools has risen exponentially in recent years as an innovative method to reveal the role of social networks in education. However, scholars are still exploring ways to incorporate traditional quantitative methods of Social Network Analysis (SNA) with qualitative approaches to social network research. This…
Baker-Doyle, Kira J.
Social network research on teachers and schools has risen exponentially in recent years as an innovative method to reveal the role of social networks in education. However, scholars are still exploring ways to incorporate traditional quantitative methods of Social Network Analysis (SNA) with qualitative approaches to social network research. This…
Lindqvist Appell, Malin; Mårtensson, Lars-Göran; Almer, Sven; Peterson, Curt
Thiopurines are chemotherapeutic drugs used for treatment of inflammatory bowel diseases and childhood leukemia. Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurines. Individuals lacking TPMT are at increased risk for severe side effects when treated with conventional doses of thiopurines. A research group at the division of drug research at Linköping University is studying thiopurine pharmacogenetics. Since the year 2000, the lab has determined the TPMT status in over 12000 individuals, as an aid to decide thiopurine doses before starting treatment. New knowledge of how genetic factors influence thiopurine treatment effect are anticipated to improve the possibilities for individualization of thiopurine therapy.
Kudzi, W; Addy, B S; Dzudzor, B
Pharmacogenetics has a potential for optimizing drug response and identifying risk of toxicity for patients. Pharmacogenetics knowledge of healthcare professionals and the unmet need for pharmacogenetics education in health training institutions are some of the challenges of integrating pharmacogenetics into routine medical practice. To assess pharmacogenetics knowledge among healthcare professionals and faculty members of health training institutions in Ghana. Semi-structured questionnaires were used to interview healthcare professionals from selected public and private hospitals. Faculty members from health training institutions were also interviewed. The respondents were Medical doctors 42 (46.7%), Pharmacists 29 (32.2%) and Nurses 19 (21.1%). Healthcare professionals rated their knowledge of Pharmacogenetics as Excellent 5 (5.6%), Very Good 10 (11.2%), Good 53 (60%) and Poor 19 (21.4%). Thirty-two faculty members from health training institutions were also interviewed. Faculty members rated their knowledge of pharmacogenetics as Excellent 2 (6.3%), Very Good 3 (9.4%), Good 9 (28.1%), Fair 12 (37.5%) and Poor 6 (18.8%). Thirty seven percent (12) of these faculty members said pharmacogenetics was not part of their institutions' curriculum, 7 (22%) did not know if pharmacogenetics was part of their curriculum and only 13 (40.6%) said it was part of their curriculum. Few healthcare professionals and faculty members of training institutions are aware of the discipline of pharmacogenetics. There is the need for continuous professional education on pharmacogenetics and development of competency standards for all healthcare professionals in Ghana.
Hertz, Daniel L; Luzum, Jasmine A; Pasternak, Amy L; Ward, Kristen M; Zhu, Hao-Jie; Rae, James M; Ellingrod, Vicki L
The University of Michigan College of Pharmacy has made substantial investment in the area of pharmacogenomics to further bolster its activity in pharmacogenomics research, implementation and education. Four tenure-track faculty members have active research programs that focus primarily on the discovery of functional polymorphisms (HJ Zhu), and genetic associations with treatment outcomes in patients with cancer (DL Hertz), cardiovascular disease (JA Luzum) and psychiatric conditions (VL Ellingrod). Recent investments from the University and the College have accelerated the implementation of pharmacogenetics broadly across the institution and in targeted therapeutic areas. Students within the PharmD and other health science professions receive substantial instruction in pharmacogenomics, in preparation for careers in biomedical health in which they can contribute to the generation, dissemination and utilization of pharmacogenomics knowledge to improve patient care.
Demotes-Mainard, J; Kubiak, C
Evaluating research outcomes requires multinational cooperation in clinical research for optimization of treatment strategies and comparative effectiveness research, leading to evidence-based practice and healthcare cost containment. The European Clinical Research Infrastructures Network (ECRIN) is a distributed ESFRI (European Strategy Forum on Research Infrastructures) roadmap pan-European infrastructure designed to support multinational clinical research, making Europe a single area for clinical studies, taking advantage of its population size to access patients, and unlocking latent scientific potential. Servicing multinational trials started during its preparatory phase, and ECRIN will now apply for an ERIC (European Research Infrastructures Consortium) status by 2011. By creating a single area for clinical research in Europe, this achievement will contribute to the implementation of the Europe flagship initiative 2020 'Innovation Union', whose objectives include defragmentation of the research and education capacity, tackling the major societal challenges starting with the area of healthy ageing, and removing barriers to bring ideas to the market.
David, Sean P; Johnstone, Elaine C; Churchman, Michael; Aveyard, Paul; Murphy, Michael F G; Munafò, Marcus R
Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that 'one size fits all' smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice. New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach. By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed. The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.
Lythgoe, Hanna; Price, Victoria; Poustie, Vanessa; Attar, Sabah; Hawcutt, Daniel; Preston, Jennifer; Beresford, Michael W
This review provides paediatricians with an update on the new structure of the National Institute for Health Research's (NIHR) Clinical Research Network (CRN): Children and its role within the wider NIHR infrastructure. The network supports delivery of high-quality research within the NHS in England and supports researchers, through provision of staff and resources, with feasibility, site set-up, patient recruitment and study management. Since 2013, over 80% of commercial contract studies running within the UK sat within the UKCRN Portfolio. Of the diverse, increasing portfolio of studies supported by the network, many studies are interventional, with 33% being randomised controlled studies. Recruitment to studies supported by the network through the Children's Portfolio has consistently improved. Over 200 000 participants have been recruited to the Children's Portfolio studies to date, and there are currently approximately 500 studies open to recruitment. The CRN: Children has successfully involved patients and the public in all aspects of study design and delivery, including through the work of Generation R. Challenges remain in conducting paediatric research and the network is committed to supporting Children's research and further building on its achievements to date. Education and engagement of paediatricians within the network and research is important to further improving quality and delivery of paediatric research. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Daugherty, Sarah E; Wahba, Sarita; Fleurence, Rachael
The Patient-Centered Outcomes Research Institute (PCORI) recently launched PCORnet to establish a single inter-operable multicenter data research network that will support observational research and randomized clinical trials. This paper provides an overview of the patient-powered research networks (PPRNs), networks of patient organizations focused on a particular health condition that are interested in sharing health information and engaging in research. PPRNs will build on their foundation of trust within the patient communities and draw on their expertise, working with participants to identify true patient-centered outcomes and direct a patient-centered research agenda. The PPRNs will overcome common challenges including enrolling a diverse and representative patient population; engaging patients in governance; designing the data infrastructure; sharing data securely while protecting privacy; prioritizing research questions; scaling small networks into a larger network; and identifying pathways to sustainability. PCORnet will be the first distributed research network to bring PCOR to national scale. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
CHANG, KU-LANG; WEITZEL, KRISTIN; SCHMIDT, SIEGFRIED
Clinical pharmacogenetics, the use of genetic data to guide drug therapy decisions, is beginning to be used for medications commonly prescribed by family physicians. However, clinicians are largely unfamiliar with principles supporting clinical use of this type of data. For example, genetic variability in the cytochrome P450 2D6 drug metabolizing enzyme can alter the clinical effects of some opioid analgesics (e.g., codeine, tramadol), whereas variability in the CYP2C19 enzyme affects the antiplatelet agent clopidogrel. If testing is performed, patients who are ultrarapid or poor metabolizers of CYP2D6 should avoid codeine use (and possibly tramadol, hydrocodone, and oxycodone) because of the potential for increased toxicity or lack of effectiveness. Patients undergoing percutaneous coronary intervention for acute coronary syndromes who are known to be poor metabolizers of CYP2C19 should consider alternate antiplatelet therapy (e.g., ticagrelor, prasugrel). Some guidelines are available that address appropriate drug therapy changes, and others are in development. Additionally, a number of clinical resources are emerging to support family physicians in the use of pharmacogenetics. When used appropriately, pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects. PMID:26447442
Haile, Colin N; Kosten, Thomas R; Kosten, Therese A
Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders. To review how genetic variation affects responses to cocaine, amphetamine, and methamphetamine and how this information may guide pharmacotherapy. We performed a cross-referenced literature search on pharmacogenetics, cocaine, amphetamine, and methamphetamine. We describe functional genetic variants for enzymes dopamine-beta-hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and dopamine transporter (DAT1), dopamine D4 receptor, and brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP; C-1021T) in the DbetaH gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction. Individuals with variable number tandem repeats (VNTR) of the SLC6A3 gene 3'-untranslated region polymorphism of DAT1 have altered responses to drugs. The 10/10 repeat respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant show blunted euphoria and physiological response to amphetamine. COMT, D4 receptor, and BDNF polymorphisms are linked to methamphetamine abuse and psychosis. Disulfiram and methylphenidate pharmacotherapies for cocaine addiction are optimized by considering polymorphisms affecting DbetaH and DAT1 respectively. Altered subjective effects for amphetamine in DAT1 VNTR variants suggest a 'protected' phenotype. Pharmacogenetic-based treatments for psychostimulant addiction are critical for successful treatment.
Singh, Shalini; Usman, Kauser; Banerjee, Monisha
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment. PMID:27555891
Fabbri, Chiara; Minarini, Alessandro; Niitsu, Tomihisa; Serretti, Alessandro
The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p < 0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect. In order to improve the understanding of SSRI pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.
Our knowledge of pharmacogenetic variability in diverse populations is scarce, especially in sub-Saharan Africa. To bridge this gap in knowledge, we characterised population frequencies of clinically relevant pharmacogenetic traits in two distinct South African population groups. We genotyped 211 tagging single nucleotide polymorphisms (tagSNPs) in 12 genes that influence antiretroviral drug disposition, in 176 South African individuals belonging to two distinct population groups residing in the Western Cape: the Xhosa (n = 109) and Cape Mixed Ancestry (CMA) (n = 67) groups. The minor allele frequencies (MAFs) of eight tagSNPs in six genes (those encoding the ATP binding cassette sub-family B, member 1 [ABCB1], four members of the cytochrome P450 family [CYP2A7P1, CYP2C18, CYP3A4, CYP3A5] and UDP-glucuronosyltransferase 1 [UGT1A1]) were significantly different between the Xhosa and CMA populations (Bonferroni p < 0.05). Twenty-seven haplotypes were inferred in four genes (CYP2C18, CYP3A4, the gene encoding solute carrier family 22 member 6 [SLC22A6] and UGT1A1) between the two South African populations. Characterising the Xhosa and CMA population frequencies of variant alleles important for drug transport and metabolism can help to establish the clinical relevance of pharmacogenetic testing in these populations. PMID:21712189
Law, B E
Research involves analysis and field direction of AmeriFlux operations, and the PI provides scientific leadership of the AmeriFlux network. Activities include the coordination and quality assurance of measurements across AmeriFlux network sites, synthesis of results across the network, organizing and supporting the annual Science Team Meeting, and communicating AmeriFlux results to the scientific community and other users. Objectives of measurement research include (i) coordination of flux and biometric measurement protocols (ii) timely data delivery to the Carbon Dioxide Information and Analysis Center (CDIAC); and (iii) assurance of data quality of flux and ecosystem measurements contributed by AmeriFlux sites. Objectives of integration and synthesis activities include (i) integration of site data into network-wide synthesis products; and (ii) participation in the analysis, modeling and interpretation of network data products. Communications objectives include (i) organizing an annual meeting of AmeriFlux investigators for reporting annual flux measurements and exchanging scientific information on ecosystem carbon budgets; (ii) developing focused topics for analysis and publication; and (iii) developing data reporting protocols in support of AmeriFlux network goals.
Bacon, Charles; Bell, Greg; Canon, Shane; Dart, Eli; Dattoria, Vince; Goodwin, Dave; Lee, Jason; Hicks, Susan; Holohan, Ed; Klasky, Scott; Lauzon, Carolyn; Rogers, Jim; Shipman, Galen; Skinner, David; Tierney, Brian
The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet to be a highly successful enabler of scientific discovery for over 25 years. In October 2012, ESnet and the Office of Advanced Scientific Computing Research (ASCR) of the DOE SC organized a review to characterize the networking requirements of the programs funded by the ASCR program office. The requirements identified at the review are summarized in the Findings section, and are described in more detail in the body of the report.
Chaoqi, Fu; Ying, Wang; Xiaoyang, Wang
In reality, most of the topological structures of complex networks are not ideal. Considering the restrictions from all aspects, we cannot timely adjust and improve network defects. Once complex networks collapse under cascading failure, an appropriate repair strategy must be implemented. This repair process is divided into 3 kinds of situations. Based on different types of opening times, we presented 2 repair modes, and researched 4 kinds of repair strategies. Results showed that network efficiency recovered faster when the repair strategies were arranged in descending order by parameters under the immediate opening condition. However, the risk of secondary failure and additional expansion capacity were large. On the contrary, when repair strategies were in ascending order, the demand for additional capacity caused by secondary failure was greatly saved, but the recovery of network efficiency was relatively slow. Compared to immediate opening, delayed opening alleviated the contradiction between network efficiency and additional expansion capacity, particularly to reduce the risk of secondary failure. Therefore, different repair methods have different repair characteristics. This paper investigates the impact of cascading effects on the network repair process, and by presenting a detailed description of the status of each repaired node, helps us understand the advantages and disadvantages of different repair strategies.
Kahlon, Maninder; Yuan, Leslie; Daigre, John; Meeks, Eric; Nelson, Katie; Piontkowski, Cynthia; Reuter, Katja; Sak, Rachael; Turner, Brian; Weber, Griffin M; Chatterjee, Anirvan
Universities have begun deploying public Internet systems that allow for easy search of their experts, expertise, and intellectual networks. Deployed first in biomedical schools but now being implemented more broadly, the initial motivator of these research networking systems was to enable easier identification of collaborators and enable the development of teams for research. The intent of the study was to provide the first description of the usage of an institutional research "social networking" system or research networking system (RNS). Number of visits, visitor location and type, referral source, depth of visit, search terms, and click paths were derived from 2.5 years of Web analytics data. Feedback from a pop-up survey presented to users over 15 months was summarized. RNSs automatically generate and display profiles and networks of researchers. Within 2.5 years, the RNS at the University of California, San Francisco (UCSF) achieved one-seventh of the monthly visit rate of the main longstanding university website, with an increasing trend. Visitors came from diverse locations beyond the institution. Close to 75% (74.78%, 208,304/278,570) came via a public search engine and 84.0% (210 out of a sample of 250) of these queried an individual's name that took them directly to the relevant profile page. In addition, 20.90% (214 of 1024) visits went beyond the page related to a person of interest to explore related researchers and topics through the novel and networked information provided by the tool. At the end of the period analyzed, more than 2000 visits per month traversed 5 or more links into related people and topics. One-third of visits came from returning visitors who were significantly more likely to continue to explore networked people and topics (P<.001). Responses to an online survey suggest a broad range of benefits of using the RNS in supporting the research and clinical mission. Returning visitors in an ever-increasing pool of visitors to an RNS are
Cepuder, Peter; Nolz, Reinhard; Bohner, Andreas; Baumgarten, Andreas; Klammler, Gernot; Murer, Erwin; Wimmer, Bernhard
A lysimeter is a vessel that isolates a volume of soil between ground surface and a certain depth, and includes a sampling device for percolating water at its bottom. Lysimeters are traditionally used to study water and solute transport in the soil. Equipped with a weighing system, soil water sensors and temperature sensors, lysimeters are valuable instruments to investigate hydrological processes in the system soil-plant-atmosphere, especially fluxes across its boundary layers, e.g. infiltration, evapotranspiration and deep drainage. Modern lysimeter facilities measure water balance components with high precision and high temporal resolution. Hence, lysimeters are used in various research disciplines - such as hydrology, hydrogeology, soil science, agriculture, forestry, and climate change studies - to investigate hydrological, chemical and biological processes in the soil. The Lysimeter Research Group (LRG) was established in 1992 as a registered nonprofit association with free membership (ZVR number: 806128239, Austria). It is organized as an executive board with an international scientific steering committee. In the beginning the LRG focused mainly on nitrate contamination in Austria and its neighboring countries. Today the main intention of the LRG is to advance interdisciplinary exchange of information between researchers and users working in the field of lysimetry on an international level. The LRG also aims for the dissemination of scientific knowledge to the public and the support of decision makers. Main activities are the organization of a lysimeter conference every two years in Raumberg-Gumpenstein (Styria, Austria), the organization of excursions to lysimeter stations and related research sites around Europe, and the maintenance of a website (www.lysimeter.at). The website contains useful information about numerous European lysimeter stations regarding their infrastructure, instrumentation and operation, as well as related links and references which
Xu, Yingying; Zou, Shengrong; Gu, Aihua; Wei, Li; Zhou, Ta
The UNSPSC ontology mainly applies to the classification system of the e-business and governments buying the worldwide products and services, and supports the logic structure of classification of the products and services. In this paper, the related technologies of the complex network were applied to analyzing the structure of the ontology. The concept of the ontology was corresponding to the node of the complex network, and the relationship of the ontology concept was corresponding to the edge of the complex network. With existing methods of analysis and performance indicators in the complex network, analyzing the degree distribution and community of the ontology, and the research will help evaluate the concept of the ontology, classify the concept of the ontology and improve the efficiency of semantic matching.
Meir, Karen; Gaffney, Eoin F; Simeon-Dubach, Daniel; Ravid, Rivka; Watson, Peter H; Schacter, Brent; Morente And The Marble Arch International Working Group On Biobanking, Manuel M
The biobanking literature frequently addresses donor and societal issues surrounding biobanking, but the biobanker's perspective is rarely highlighted. While not comprehensive, this article offers an overview of the human aspects of biobanking from the viewpoint of biobank personnel-from biobank formation, through the process, and in addressing post-biobanking issues. As every biobank and biobank network may differ, such factors may vary. Before biobanking can commence, the purpose of the biobank network must be defined, and buy-in achieved from many stakeholders. An attitude of trust and sharing is essential, as is good communication. Developing a biobank is time consuming and laborious. Forming a network requires significantly more time due to the need for cross-institutional harmonization of policies, procedures, information technology considerations, and ethics. Circumstances may dictate whether development occurs top-down and/or bottom-up, as well as whether network management may be independent or by personnel from participating biobanks. Funding tends to be a prominent issue for biobanks and networks alike. In particular, networks function optimally with some level of government support, particularly for personnel. Quality biospecimen collection involves meticulously documented coordination with a network of medical and nursing staff. Examining and sampling operative specimens requires timely collaboration between the surgical and pathology teams. "Catch rates" for samples may be difficult to predict and may occur at a frequency less than anticipated due to factors related to the institution, staff, or specimen. These factors may affect specimen quality, and have a downstream effect on competition for specimens for research. Thus, release of samples requires a fair, carefully constructed sample access policy, usually incorporating an incentive for researchers, and an encouragement to form collaborations. Finally, the public and patient groups should aim to
Giardini, Domenico; van Eck, Torild; Bossu, Rémy; Wiemer, Stefan
In the past decade, European countries have experienced a surge in funding, of the order of 100 million euro (€100 million), for new earthquake monitoring equipment and initiatives. Permanent and mobile seismograph and accelerometer networks on national, regional, and global levels are being modernized and are expanding at a significant pace. Currently, earthquakes in the European-Mediterranean region are recorded by more than 2500 short-period (SP) seismometers, 3000 accelerometers, and 800 broadband (BB) permanent seismic stations operated by more than 100 networks and observatories. An additional 400 BB and more than 1200 SP mobile stations are deployed by universities and research institutes in temporary experiments. This unprecedented and still-expanding recording capacity in Europe and its immediate surroundings opens up new research opportunities as well as new data-handling challenges. For example, maintaining optimum access to the data and integrating facilities with different types of data require a high level of networking and coordination.
Hanauer, David I; Hatfull, Graham
The aim of this paper is to propose, present, and validate a simple survey instrument to measure student conversational networking. The tool consists of five items that cover personal and professional social networks, and its basic principle is the self-reporting of degrees of conversation, with a range of specific discussion partners. The networking instrument was validated in three studies. The basic psychometric characteristics of the scales were established by conducting a factor analysis and evaluating internal consistency using Cronbach's alpha. The second study used a known-groups comparison and involved comparing outcomes for networking scales between two different undergraduate laboratory courses (one involving a specific effort to enhance networking). The final study looked at potential relationships between specific networking items and the established psychosocial variable of project ownership through a series of binary logistic regressions. Overall, the data from the three studies indicate that the networking scales have high internal consistency (α = 0.88), consist of a unitary dimension, can significantly differentiate between research experiences with low and high networking designs, and are related to project ownership scales. The ramifications of the networking instrument for student retention, the enhancement of public scientific literacy, and the differentiation of laboratory courses are discussed. © 2015 D. I. Hanauer and G. Hatfull. CBE—Life Sciences Education © 2015 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
Anderson, Katharine A.; Crespi, Matthew; Sayre, Eleanor C.
There is considerable long-term interest in understanding the dynamics of collaboration networks, and how these networks form and evolve over time. Most of the work done on the dynamics of social networks focuses on well-established communities. Work examining emerging social networks is rarer, simply because data are difficult to obtain in real time. In this paper, we use thirty years of data from an emerging scientific community to look at that crucial early stage in the development of a social network. We show that when the field was very young, islands of individual researchers labored in relative isolation, and the coauthorship network was disconnected. Thirty years later, rather than a cluster of individuals, we find a true collaborative community, bound together by a robust collaboration network. However, this change did not take place gradually—the network remained a loose assortment of isolated individuals until the mid 2000s, when those smaller parts suddenly knit themselves together into a single whole. In the rest of this paper, we consider the role of three factors in these observed structural changes: growth, changes in social norms, and the introduction of institutions such as field-specific conferences and journals. We have data from the very earliest years of the field, a period which includes the introduction of two different institutions: the first field-specific conference, and the first field-specific journals. We also identify two relevant behavioral shifts: a discrete increase in coauthorship coincident with the first conference, and a shift among established authors away from collaborating with outsiders, towards collaborating with each other. The interaction of these factors gives us insight into the formation of collaboration networks more broadly.
Laditka, James N.; Beard, Renee L.; Bryant, Lucinda L.; Fetterman, David; Hunter, Rebecca; Ivey, Susan; Logsdon, Rebecca G.; Sharkey, Joseph R.; Wu, Bei
Purpose: Evidence suggests that healthy lifestyles may help maintain cognitive health. The Prevention Research Centers Healthy Aging Research Network, 9 universities collaborating with their communities and the Centers for Disease Control and Prevention, is conducting a multiyear research project, begun in 2005, to understand how to translate this…
Sydne Record; Paige F. B. Ferguson; Elise Benveniste; Rose A. Graves; Vera W. Pfeiffer; Michele Romolini; Christie E. Yorke; Ben Beardmore
Interdisciplinary, collaborative research capable of capturing the feedbacks between biophysical and social systems can improve the capacity for sustainable environmental decision making. Networks of researchers provide unique opportunities to foster social-ecological inquiry. Although insights into interdisciplinary research have been discussed elsewhere,...
Bradley, Loretta J.; Sexton, Thomas L.; Smith, Howard B.
This article features the American Counseling Association Practice Research Network (ACA-PRN). Without additional current and ongoing research data, ACA and the counseling profession are seriously hampered when they discuss counseling outcomes. Without a sound, dynamic research base that better articulates the characteristics of practicing…
Fleurence, Rachael L; Beal, Anne C; Sheridan, Susan E; Johnson, Lorraine B; Selby, Joe V
The era of big data, loosely defined as the development and analysis of large or complex data sets, brings new opportunities to empower patients and their families to generate, collect, and use their health information for both clinical and research purposes. In 2013 the Patient-Centered Outcomes Research Institute launched a large national research network, PCORnet, that includes both clinical and patient-powered research networks. This article describes these networks, their potential uses, and the challenges they face. The networks are engaging patients, family members, and caregivers in four key ways: contributing data securely, with privacy protected; including diverse and representative groups of patients in research; prioritizing research questions, participating in research, and disseminating results; and participating in the leadership and governance of patient-powered research networks. If technical, regulatory, and organizational challenges can be overcome, PCORnet will allow research to be conducted more efficiently and cost-effectively and results to be disseminated quickly back to patients, clinicians, and delivery systems to improve patient health.
Sicard, M.; D'Amico, G.; Comerón, A.; Mona, L.; Alados-Arboledas, L.; Amodeo, A.; Baars, H.; Belegante, L.; Binietoglou, I.; Bravo-Aranda, J. A.; Fernández, A. J.; Fréville, P.; García-Vizcaíno, D.; Giunta, A.; Granados-Muñoz, M. J.; Guerrero-Rascado, J. L.; Hadjimitsis, D.; Haefele, A.; Hervo, M.; Iarlori, M.; Kokkalis, P.; Lange, D.; Mamouri, R. E.; Mattis, I.; Molero, F.; Montoux, N.; Muñoz, A.; Muñoz Porcar, C.; Navas-Guzmán, F.; Nicolae, D.; Nisantzi, A.; Papagiannopoulos, N.; Papayannis, A.; Pereira, S.; Preißler, J.; Pujadas, M.; Rizi, V.; Rocadenbosch, F.; Sellegri, K.; Simeonov, V.; Tsaknakis, G.; Wagner, F.; Pappalardo, G.
In the framework of ACTRIS summer 2012 measurement campaign (8 June-17 July 2012), EARLINET organized and performed a controlled exercise of feasibility to demonstrate its potential to perform operational, coordinated measurements and deliver products in near-real time. Eleven lidar stations participated to the exercise which started on 9 July 2012 at 06:00 UT and ended 72 h later on 12 July at 06:00 UT. For the first time the Single-Calculus Chain (SCC), the common calculus chain developed within EARLINET for the automatic evaluation of lidar data from raw signals up to the final products, was used. All stations sent in real time measurements of 1 h of duration to the SCC server in a predefined netcdf file format. The pre-processing of the data was performed in real time by the SCC while the optical processing was performed in near-real time after the exercise ended. 98 and 84 % of the files sent to SCC were successfully pre-processed and processed, respectively. Those percentages are quite large taking into account that no cloud screening was performed on lidar data. The paper shows time series of continuous and homogeneously obtained products retrieved at different levels of the SCC: range-square corrected signals (pre-processing) and daytime backscatter and nighttime extinction coefficient profiles (optical processing), as well as combined plots of all direct and derived optical products. The derived products include backscatter- and extinction-related Ångström exponents, lidar ratios and color ratios. The combined plots reveal extremely valuable for aerosol classification. The efforts made to define the measurements protocol and to configure properly the SCC pave the way for applying this protocol for specific applications such as the monitoring of special events, atmospheric modelling, climate research and calibration/validation activities of spaceborne observations.
De Jager-Loftus, Danielle P; Midyette, J David; Harvey, Barbara
Providing library and reference services within a biomedical research community presents special challenges for librarians, especially those in historically lower-funded states. These challenges can include understanding needs, defining and communicating the library's role, building relationships, and developing and maintaining general and subject specific knowledge. This article describes a biomedical research network and the work of health sciences librarians at the lead intensive research institution with librarians from primarily undergraduate institutions and tribal colleges. Applying the concept of a community of practice to a collaborative effort suggests how librarians can work together to provide effective reference services to researchers in biomedicine.
This dissertation covers the two major parts of my Ph.D. research: i) developing a theoretical framework of complex networks and applying simulation and numerical methods to study the robustness of the network system, and ii) applying statistical physics concepts and methods to quantitatively analyze complex systems and applying the theoretical framework to study real-world systems. In part I, we focus on developing theories of interdependent networks as well as building computer simulation models, which includes three parts: 1) We report on the effects of topology on failure propagation for a model system consisting of two interdependent networks. We find that the internal node correlations in each of the networks significantly changes the critical density of failures, which can trigger the total disruption of the two-network system. Specifically, we find that the assortativity within a single network decreases the robustness of the entire system. 2) We study the percolation behavior of two interdependent scale-free (SF) networks under random failure of 1-p fraction of nodes. We find that as the coupling strength q between the two networks reduces from 1 (fully coupled) to 0 (no coupling), there exist two critical coupling strengths q1 and q2 , which separate the behaviors of the giant component as a function of p into three different regions, and for q2 < q < q 1 , we observe a hybrid order phase transition phenomenon. 3) We study the robustness of n interdependent networks with partially support-dependent relationship both analytically and numerically. We study a starlike network of n Erdos-Renyi (ER), SF networks and a looplike network of n ER networks, and we find for starlike networks, their phase transition regions change with n, but for looplike networks the phase regions change with average degree k . In part II, we apply concepts and methods developed in statistical physics to study economic systems. We analyze stock market indices and foreign exchange
Tankard, James W.; And Others
Reviews citation networks and discovers that the six major areas of activity in mass communication research are (1) television and politics, (2) sociological studies of journalists, (3) agenda setting, (4) the effects of mass communication, (5) the credibility of various news media, and (6) the characteristics of users and nonusers of mass media.…
Suggests that artificial neural networks (ANNs) exhibit properties that promise usefulness for policy researchers. Notes that ANNs have found extensive use in areas once reserved for multivariate statistical programs such as regression and multiple classification analysis and are developing an extensive community of advocates for processing text…
Hansen, Richard A.; Zeng, Peng; Ryan, Patrick; Gao, Juan; Sonawane, Kalyani; Teeter, Benjamin; Westrich, Kimberly; Dubois, Robert W.
Distributed data networks representing large diverse populations are an expanding focus of drug safety research. However, interpreting results is difficult when treatment effect estimates vary across datasets (i.e., heterogeneity). In a previous study, risk estimates were generated for selected drugs and potential adverse outcomes. Analyses were…
Suggests that artificial neural networks (ANNs) exhibit properties that promise usefulness for policy researchers. Notes that ANNs have found extensive use in areas once reserved for multivariate statistical programs such as regression and multiple classification analysis and are developing an extensive community of advocates for processing text…
Participatory web-based technologies have the potential to change the way scholars engage in scholarship. One reason Web 2.0 technologies, such as online social networking, are not widely integrated in PreK-12 and postsecondary education is the lack of modeling by educators. Their lack of research-based best practices limits the ability to…
The Educational Research Forum on the CompuServe communication network consists of three parts. The online conferencing area enables users to communicate by typing messages. Communication may be private or stored in the electronic journal for other users to read. The bulletin board, or electronic mail, enables users to send or receive messages.…
Hansen, Richard A.; Zeng, Peng; Ryan, Patrick; Gao, Juan; Sonawane, Kalyani; Teeter, Benjamin; Westrich, Kimberly; Dubois, Robert W.
Distributed data networks representing large diverse populations are an expanding focus of drug safety research. However, interpreting results is difficult when treatment effect estimates vary across datasets (i.e., heterogeneity). In a previous study, risk estimates were generated for selected drugs and potential adverse outcomes. Analyses were…
This article reviews literature on the potential for understanding higher education change processes through social network analysis (SNA). In this article, the main tenets of SNA are reviewed and, in conjunction with organizational theory, are applied to higher education change to develop a set of hypotheses that can be tested in future research.
This article reviews literature on the potential for understanding higher education change processes through social network analysis (SNA). In this article, the main tenets of SNA are reviewed and, in conjunction with organizational theory, are applied to higher education change to develop a set of hypotheses that can be tested in future research.
Tran, Clara Y.; Lyon, Jennifer A.
This cross-sectional survey focused on faculty use and knowledge of author identifiers and researcher networking systems, and professional use of social media, at a large state university. Results from 296 completed faculty surveys representing all disciplines (9.3% response rate) show low levels of awareness and variable resource preferences. The…
Swan, William W., Ed.; Brown, Carvin L., Ed.
This research report contains seven papers on students with serious Emotional Disturbances (SED) and/or Severe Behavior Disorder (SBD) who participated in the Georgia Psychoeducational Network Program (GPN). "The 1982 Cohort of GPN Preschoolers--Where Are They in 1987-1988?" (Juanda Ponsell and others) reports the placement of 75…
Worrall, Lisa; Harris, Katy
This article outlines the first cycle of an Action Research (AR) investigation into why professional learners are not using the Social Networking Technologies (SNTs) of their bespoke website. It presents the rationale of how this study came about, the ontological and epistemological stance of the authors and how this led to the particular choice…
The water cycle in alpine environments worldwide supplies fresh water to vast downstream areas inhabited by more than half of humanity. The International Network for Alpine Research Catchment Hydrology (INARCH) was launched this year by the Global Energy and Water Exchanges project of the World Clim...
Abraham, Amanda J.; Knudsen, Hannah K.; Rothrauff, Tanja C.; Roman, Paul M.
Organizational participation in clinical research may lead to adoption of the intervention by treatment agencies, but it is not known whether research involvement enhances innovativeness beyond the specific interventions that are tested. The National Institute on Drug Abuse’s (NIDA) Clinical Trial Network (CTN) is a platform for considering this research question. To date, the CTN has not conducted research on medications for alcohol use disorders (AUDs), so greater adoption of innovative AUD pharmacotherapies by CTN-affiliated programs would suggest an added value of research network participation. Using longitudinal data from a pooled sample of CTN and non-CTN publicly funded treatment programs, we investigate adoption of tablet naltrexone and acamprosate over a two-year period. CTN-affiliated programs were more likely to have adopted tablet naltrexone and acamprosate at 24-month follow-up, net of the effects of a range of organizational characteristics. Research network participation may thus enhance organizational innovativeness to include interventions beyond the scope of the network. PMID:20117908
Background Leadership behaviour in complex networks is under-researched, and little has been written concerning leadership of translational research networks (TRNs) that take discoveries made ‘at the bench’ and translate them into practices used ‘at the bedside.’ Understanding leaders’ opportunities and behaviours within TRNs working to solve this key problem in implementing evidence into clinical practice is therefore important. This study explored the network position of governing body members and perceptions of their role in a new TRN in Sydney, Australia. The paper asks three questions: Firstly, do the formal, mandated leaders of this TRN hold key positions of centrality or brokerage in the informal social network of collaborative ties? Secondly, if so, do they recognise the leadership opportunities that their network positions afford them? Thirdly, what activities associated with these key roles do they believe will maximise the TRN’s success? Methods Semi-structured interviews of all 14 governing body members conducted in early 2012 explored perceptions of their roles and sought comments on a list of activities drawn from review of successful transdisciplinary collaboratives combined with central and brokerage roles. An on-line, whole network survey of all 68 TRN members sought to understand and map existing collaborative connections. Leaders’ positions in the network were assessed using UCInet, and graphs were generated in NetDraw. Results Social network analysis identified that governing body members had high centrality and high brokerage potential in the informal network of work-related ties. Interviews showed perceived challenges including ‘silos’ and the mismatch between academic and clinical goals of research. Governing body members recognised their central positions, which would facilitate the leadership roles of leading, making decisions, and providing expert advice necessary for the co-ordination of effort and relevant input across
Long, Janet C; Cunningham, Frances C; Wiley, Janice; Carswell, Peter; Braithwaite, Jeffrey
Leadership behaviour in complex networks is under-researched, and little has been written concerning leadership of translational research networks (TRNs) that take discoveries made 'at the bench' and translate them into practices used 'at the bedside.' Understanding leaders' opportunities and behaviours within TRNs working to solve this key problem in implementing evidence into clinical practice is therefore important. This study explored the network position of governing body members and perceptions of their role in a new TRN in Sydney, Australia. The paper asks three questions: Firstly, do the formal, mandated leaders of this TRN hold key positions of centrality or brokerage in the informal social network of collaborative ties? Secondly, if so, do they recognise the leadership opportunities that their network positions afford them? Thirdly, what activities associated with these key roles do they believe will maximise the TRN's success? Semi-structured interviews of all 14 governing body members conducted in early 2012 explored perceptions of their roles and sought comments on a list of activities drawn from review of successful transdisciplinary collaboratives combined with central and brokerage roles. An on-line, whole network survey of all 68 TRN members sought to understand and map existing collaborative connections. Leaders' positions in the network were assessed using UCInet, and graphs were generated in NetDraw. Social network analysis identified that governing body members had high centrality and high brokerage potential in the informal network of work-related ties. Interviews showed perceived challenges including 'silos' and the mismatch between academic and clinical goals of research. Governing body members recognised their central positions, which would facilitate the leadership roles of leading, making decisions, and providing expert advice necessary for the co-ordination of effort and relevant input across domains. Brokerage potential was recognised
Yuan, Leslie; Daigre, John; Meeks, Eric; Nelson, Katie; Piontkowski, Cynthia; Reuter, Katja; Sak, Rachael; Turner, Brian; Weber, Griffin M; Chatterjee, Anirvan
Background Universities have begun deploying public Internet systems that allow for easy search of their experts, expertise, and intellectual networks. Deployed first in biomedical schools but now being implemented more broadly, the initial motivator of these research networking systems was to enable easier identification of collaborators and enable the development of teams for research. Objective The intent of the study was to provide the first description of the usage of an institutional research “social networking” system or research networking system (RNS). Methods Number of visits, visitor location and type, referral source, depth of visit, search terms, and click paths were derived from 2.5 years of Web analytics data. Feedback from a pop-up survey presented to users over 15 months was summarized. Results RNSs automatically generate and display profiles and networks of researchers. Within 2.5 years, the RNS at the University of California, San Francisco (UCSF) achieved one-seventh of the monthly visit rate of the main longstanding university website, with an increasing trend. Visitors came from diverse locations beyond the institution. Close to 75% (74.78%, 208,304/278,570) came via a public search engine and 84.0% (210 out of a sample of 250) of these queried an individual’s name that took them directly to the relevant profile page. In addition, 20.90% (214 of 1024) visits went beyond the page related to a person of interest to explore related researchers and topics through the novel and networked information provided by the tool. At the end of the period analyzed, more than 2000 visits per month traversed 5 or more links into related people and topics. One-third of visits came from returning visitors who were significantly more likely to continue to explore networked people and topics (P<.001). Responses to an online survey suggest a broad range of benefits of using the RNS in supporting the research and clinical mission. Conclusions Returning
Koso-Thomas, Marion; McClure, Elizabeth M
In response to the global effort to accelerate progress towards the Millennium Development Goals 4 and 5, a partnership was created between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Bill and Melinda Gates Foundation to establish the Global Network for Women's and Children's Health Research (Global Network) in 2000. The Global Network was developed with a goal of building local maternal and child health research capacity in resource-poor settings. The objective of the network was to conduct research focused on several high-need areas, such as preventing life-threatening obstetric complications, improving birth weight and infant growth, and improving childbirth practices in order to reduce mortality. Scientists from developing countries, together with peers in the USA, lead research teams that identify and address population needs through randomized clinical trials and other research studies. Global Network projects develop and test cost-effective, sustainable interventions for pregnant women and newborns and provide guidance for national policy and for the practice of evidence-based medicine. This article reviews the results of the Global Network's research, the impact on policy and practice, and highlights the capacity-building efforts and collaborations developed since its inception.
Koso-Thomas, Marion; McClure, Elizabeth M.
SUMMARY In response to the global effort to accelerate progress towards the Millennium Development Goals 4 and 5, a partnership was created between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Bill and Melinda Gates Foundation to establish the Global Network for Women's and Children's Health Research (Global Network) in 2000. The Global Network was developed with a goal of building local maternal and child health research capacity in resource-poor settings. The objective of the network was to conduct research focused on several high-need areas, such as preventing life-threatening obstetric complications, improving birth weight and infant growth, and improving childbirth practices in order to reduce mortality. Scientists from developing countries, together with peers in the USA, lead research teams that identify and address population needs through randomized clinical trials and other research studies. Global Network projects develop and test cost-effective, sustainable interventions for pregnant women and newborns and provide guidance for national policy and for the practice of evidence-based medicine. This article reviews the results of the Global Network's research, the impact on policy and practice, and highlights the capacity-building efforts and collaborations developed since its inception. PMID:26043962
de Leon, José; Arranz, Maria J; Ruaño, Gualberto
This article focuses on the first generation of pharmacogenetic tests that are potentially useful in psychiatry. All pharmacogenetic tests currently on the market, or soon to be marketed in psychiatry, for which some information has been published in peer-reviewed journal articles (or abstracts), were selected. Five pharmacogenetic tests are reviewed in detail: the Roche AmpliChip CYP450 Test, the Luminex Tag-It Mutation Detection Kit, the LGC clozapine response test, the PGxPredict: Clozapine test, and the Genomas PhyzioType system. After reviewing these tests, three practical aspects of implementing pharmacogenetic testing in psychiatric clinical practice are briefly reviewed: (1) the evaluation of these tests in clinical practice, (2) cost-effectiveness, and (3) regulatory oversight. Finally, the future of these and other pharmacogenetic tests in psychiatry is discussed.
de Leon, Jose; Spina, Edoardo
This editorial considers two questions in psychopharmacotherapy: 1) What is needed to market pharmacogenetic tests in the US, since the US appears to lead other countries? and 2) What is needed for US-marketed pharmacogenetic tests to be incorporated by prescribers into long-term practice? US marketing of pharmacogenetic tests requires 1) understanding the pharmacological complexity of drug response, 2) modifying the oversight of non-FDA regulatory agencies, 3) clarifying the FDA's role and 4) promoting innovative marketing. The incorporation of pharmacogenetic tests into long-term practice requires 1) not jeopardizing pharmacogenetic testing by short-sighted marketing of non-validated tests, 2) educating prescribers about benefits, 3) educating patients about limitations and 4) considering the differences between isolated testing and generalized testing incorporating big data.
Likumahuwa, Sonja; Song, Hui; Singal, Robbie; Weir, Rosy Chang; Crane, Heidi; Muench, John; Sim, Shao-Chee; DeVoe, Jennifer E.
This article introduces the Community Health Applied Research Network (CHARN), a practice-based research network of community health centers (CHCs). Established by the Health Resources and Services Administration in 2010, CHARN is a network of 4 community research nodes, each with multiple affiliated CHCs and an academic center. The four nodes (18 individual CHCs and 4 academic partners in 9 states) are supported by a data coordinating center. Here we provide case studies detailing how CHARN is building research infrastructure and capacity in CHCs, with a particular focus on how community practice-academic partnerships were facilitated by the CHARN structure. The examples provided by the CHARN nodes include many of the building blocks of research capacity: communication capacity and “matchmaking” between providers and researchers; technology transfer; research methods tailored to community practice settings; and community institutional review board infrastructure to enable community oversight. We draw lessons learned from these case studies that we hope will serve as examples for other networks, with special relevance for community-based networks seeking to build research infrastructure in primary care settings. PMID:24004710
Curtis, Brenda L
Social networking sites and online advertising organizations provide HIV/AIDS researchers access to target populations, often reaching difficult-to-reach populations. However, this benefit to researchers raises many issues for the protections of prospective research participants. Traditional recruitment procedures have involved straightforward transactions between the researchers and prospective participants; online recruitment is a more complex and indirect form of communication involving many parties engaged in the collecting, aggregating, and storing of research participant data. Thus, increased access to online data has challenged the adequacy of current and established procedures for participants' protections, such as informed consent and privacy/confidentiality. Internet-based HIV/AIDS research recruitment and its ethical challenges are described, and research participant safeguards and best practices are outlined.
Curtis, Brenda L.
Social networking sites and online advertising organizations provide HIV/AIDS researchers access to target populations, often reaching difficult-to-reach populations. However, this benefit to researchers raises many issues for the protections of prospective research participants. Traditional recruitment procedures have involved straightforward transactions between the researchers and prospective participants; online recruitment is a more complex and indirect form of communication involving many parties engaged in the collecting, aggregating, and storing of research participant data. Thus, increased access to online data has challenged the adequacy of current and established procedures for participants’ protections, such as informed consent and privacy/confidentiality. Internet-based HIV/AIDS research recruitment and its ethical challenges are described, and research participant safeguards and best practices are outlined. PMID:24572084
Costa, Daniel G; Guedes, Luiz Affonso; Vasques, Francisco; Portugal, Paulo
The development of wireless sensor networks for control and monitoring functions has created a vibrant investigation scenario, where many critical topics, such as communication efficiency and energy consumption, have been investigated in the past few years. However, when sensors are endowed with low-power cameras for visual monitoring, a new scope of challenges is raised, demanding new research efforts. In this context, the resource-constrained nature of sensor nodes has demanded the use of prioritization approaches as a practical mechanism to lower the transmission burden of visual data over wireless sensor networks. Many works in recent years have considered local-level prioritization parameters to enhance the overall performance of those networks, but global-level policies can potentially achieve better results in terms of visual monitoring efficiency. In this paper, we make a broad review of some recent works on priority-based optimizations in wireless visual sensor networks. Moreover, we envisage some research trends when exploiting prioritization, potentially fostering the development of promising optimizations for wireless sensor networks composed of visual sensors.
Costa, Daniel G.; Guedes, Luiz Affonso; Vasques, Francisco; Portugal, Paulo
The development of wireless sensor networks for control and monitoring functions has created a vibrant investigation scenario, where many critical topics, such as communication efficiency and energy consumption, have been investigated in the past few years. However, when sensors are endowed with low-power cameras for visual monitoring, a new scope of challenges is raised, demanding new research efforts. In this context, the resource-constrained nature of sensor nodes has demanded the use of prioritization approaches as a practical mechanism to lower the transmission burden of visual data over wireless sensor networks. Many works in recent years have considered local-level prioritization parameters to enhance the overall performance of those networks, but global-level policies can potentially achieve better results in terms of visual monitoring efficiency. In this paper, we make a broad review of some recent works on priority-based optimizations in wireless visual sensor networks. Moreover, we envisage some research trends when exploiting prioritization, potentially fostering the development of promising optimizations for wireless sensor networks composed of visual sensors. PMID:25599425
Cornelissen, Frank; van Swet, Jacqueline; Beijaard, Douwe; Bergen, Theo
School-university research networks aim at closer integration of research and practice by means of teacher research. Such practice-oriented research can benefit both schools and universities. This paper reports on a multiple-case study of five participants in a school-university research network in a Dutch master's program. The research question…
Skolarus, Ted A; Lehmann, Todd; Tabak, Rachel G; Harris, Jenine; Lecy, Jesse; Sales, Anne E
A recent review of frameworks used in dissemination and implementation (D&I) science described 61 judged to be related either to dissemination, implementation, or both. The current use of these frameworks and their contributions to D&I science more broadly has yet to be reviewed. For these reasons, our objective was to determine the role of these frameworks in the development of D&I science. We used the Web of Science™ Core Collection and Google Scholar™ to conduct a citation network analysis for the key frameworks described in a recent systematic review of D&I frameworks (Am J Prev Med 43(3):337-350, 2012). From January to August 2016, we collected framework data including title, reference, publication year, and citations per year and conducted descriptive and main path network analyses to identify those most important in holding the current citation network for D&I frameworks together. The source article contained 119 cited references, with 50 published articles and 11 documents identified as a primary framework reference. The average citations per year for the 61 frameworks reviewed ranged from 0.7 to 103.3 among articles published from 1985 to 2012. Citation rates from all frameworks are reported with citation network analyses for the framework review article and ten highly cited framework seed articles. The main path for the D&I framework citation network is presented. We examined citation rates and the main paths through the citation network to delineate the current landscape of D&I framework research, and opportunities for advancing framework development and use. Dissemination and implementation researchers and practitioners may consider frequency of framework citation and our network findings when planning implementation efforts to build upon this foundation and promote systematic advances in D&I science.
Background In the UK care homes are one of the main providers of long term care for older people with dementia. Despite the recent increase in care home research, residents with dementia are often excluded from studies. Care home research networks have been recommended by the Ministerial Advisory Group on Dementia Research (MAGDR) as a way of increasing research opportunities for residents with dementia. This paper reports on an evaluation of the feasibility and early impact of an initiative to increase care home participation in research. Methods A two phase, mixed methods approach was used; phase 1 established a baseline of current and recent studies including the National Institute for Health Research portfolio. To explore the experiences of recruiting care homes and research participation, interviews were conducted with researchers working for the Dementia and Neurodegenerative Diseases Research Network (DeNDRoN) and care home managers. In phase 2, four DeNDRoN area offices recruited care homes to a care home network for their region. The care home networks were separate from the DeNDRoN research network. Diaries were used to document and cost recruitment; DeNDRoN staff were interviewed to understand the barriers, facilitators and impact of the care home networks. Results Thirty three current or recent studies were identified as involving care homes as care home specific studies or those which included residents. Further details of care home recruitment were obtained on 20 studies by contacting study teams. Care home managers were keen to be involved in research that provided staff support, benefits for residents and with minimal disruption. In phase 2, 141 care homes were recruited to the care home research networks, through corporate engagement and individual invitation. Pre-existing relationships with care homes facilitated recruitment. Sites with minimal experience of working with care homes identified the need for care home training for researchers
Zai, Gwyneth; Brandl, Eva J; Müller, Daniel J; Richter, Margaret A; Kennedy, James L
Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder with high genetic influence. Antidepressants such as serotonin reuptake inhibitors, are widely accepted as the first-line medications for OCD; however, approximately 50% of OCD patients show poor response. Personalized medicine utilizing genetic testing has recently received much attention because the variability of antidepressant response and tolerability are partly due to an individual's genetic variations. This has led to researchers investigating the role of specific genetic factors on antidepressant response and utility of testing in the clinical realm. Genetic test panels are showing promise for guiding antidepressant treatment to improve outcomes in depression. This article will review the most recent findings in the pharmacogenetics of OCD and its related disorders. Promising results have been reported for several serotonergic and glutamatergic system genes and the cytochrome CYP450 liver enzyme genes, which appear to play an important role in OCD and antidepressant response.
Duconge, Jorge; Ruaño, Gualberto
Admixture is of great relevance to the clinical application of pharmacogenetics and personalized medicine. Preliminary findings in Puerto Ricans further substantiate the argument for admixture as a critical covariate in a customized DNA-guided warfarin dosing algorithm. To this purpose, a genome-wide approach that incorporates admixture as an independent predictor of dose variability in DNA-guided algorithms has been postulated. Admixture is expected to be able to reveal some relevant associations in the genetic epidemiology of Hispanics and will be indispensable to assure that pharmacogenomic research can be pursued in such mixed populations. Consequently, the clinical utility of knowing an individual’s genotype before initiating drug treatment in Puerto Ricans, and Hispanics in general, will finally be untangled by developing a “Genetic Prescription Model” that takes admixture into consideration. This approach will help lead physicians and patients to their desired treatment goal, resulting in more effective healthcare in admixed people. PMID:23227441
Abdel-Hamid, Ibrahim A; Andersson, Karl-Erik
Although treatment of different types of sexual dysfunction has improved in the past decade with the introduction of phosphodiesterase type 5 inhibitors and selective serotonin reuptake inhibitors, response rates to these targeted therapies are variable. There are a number of studies in the published literature that provide proof-of-concept that genetic variation contributes to the variable response. Pharmacogenomics will most likely be one part of our therapeutic armamentarium in the future and will provide a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution. This article will review English language medical literature on the state-of-the-art genetic polymorphisms of drug targets, transporters and signaling molecules as well as pharmacogenetic studies of sexual dysfunction and suggested possible applications. Collectively, the data demonstrate that pharmacogenomics in the field of sexual medicine is still in its infancy. More research will provide further intriguing new discoveries in years to come.
Kozapalli, S.; Warmbrodt, William (Technical Monitor)
Results from a neural network study on XV-15 tilt-rotor hover performance are presented. Two XV-15 test data bases, acquired during separate tests conducted in the National Full-Scale Aerodynamics Complex at NASA Ames, were used in this study. The two XV-15 test data bases used were: the 1997 80- by 120-Foot Wind Tunnel test data base and the 1984 Outdoor Aerodynamic Research Facility (OARF) test data base. The objectives associated with the 80- by 120-Foot Wind Tunnel test data were to conduct data quality checks, obtain neural network representations, and demonstrate sensitivity to test conditions. The objectives associated with the OARF outdoor test data were to obtain a 'zero wind' neural network representation, and formulate and implement a neural network based wind correction procedure. An additional objective, common to both test data bases, was to conduct error comparisons. The conclusions from the present study were as follows: Compared to measured parameters (i.e., collective pitch angle), derived parameters (i.e., thrust coefficient) were found preferable as neural network inputs. For the 80- by 120-Foot Wind Tunnel test data base, the neural network based figure of merit representations did not extrapolate rotor stall. Using the OARF outdoor test database, a neural network based wind correction procedure was formulated and successfully implemented. Based on an error comparison, the present neural network based wind correction procedure was found to be more accurate compared to the existing, momentum-theory-based wind correction procedure. Also, a separate error comparison showed that the 80- by 120-Foot Wind Tunnel hover performance data were comparable to non-wind-corrected outdoor test data.
Cui, Hongmei; Pei, Xichun; Ma, Hongyue; Ma, Shuoshi
A software platform of the network virtual instrument test laboratory has been developed to realize the network function of the test and signal analysis as well as the share of the hardware based on the data transmission theory and the study of the present technologies of the network virtual instrument. The whole design procedure was also presented in this paper. The main work of the research is as follows. 1. A suitable scheme of the test system with B/S mode and the virtual instrument laboratory with BSDA (Browser/Server/Database/Application) mode was determined. 2. The functions were classified and integrated by adopting the multilayer structure. The application for the virtual instruments running in the client terminal and the network management server managing the multiuser in the test laboratory according to the "Concurrent receival, sequential implementation" strategy in Java as well as the code of the test server application responding the client's requests of test and signal analysis in LabWindows/CVI were developed. As the extending part of network function of the original virtual test and analysis instruments, a software platform of network virtual instrument test laboratory was built as well. 3. The communication of the network data between Java and the LabWindows/CVI was realized. 4. The database was imported to store the data as well as the correlative information acquired by the server and help the network management server to manage the multiuser in the test laboratory. 5. A website embedding Java Applet of virtual instrument laboratory with the on-line help files was designed.
Rao, Nageswara S; Wing, William R; Poole, Stephen W; Hicks, Susan Elaine; DeNap, Frank A; Carter, Steven M; Wu, Qishi
The high-performance networking requirements for next generation large-scale applications belong to two broad classes: (a) high bandwidths, typically multiples of 10Gbps, to support bulk data transfers, and (b) stable bandwidths, typically at much lower bandwidths, to support computational steering, remote visualization, and remote control of instrumentation. Current Internet technologies, however, are severely limited in meeting these demands because such bulk bandwidths are available only in the backbone, and stable control channels are hard to realize over shared connections. The UltraScience Net (USN) facilitates the development of such technologies by providing dynamic, cross-country dedicated 10Gbps channels for large data transfers, and 150 Mbps channels for interactive and control operations. Contributions of the USN project are two-fold: (a) Infrastructure Technologies for Network Experimental Facility: USN developed and/or demonstrated a number of infrastructure technologies needed for a national-scale network experimental facility. Compared to Internet, USN's data-plane is different in that it can be partitioned into isolated layer-1 or layer-2 connections, and its control-plane is different in the ability of users and applications to setup and tear down channels as needed. Its design required several new components including a Virtual Private Network infrastructure, a bandwidth and channel scheduler, and a dynamic signaling daemon. The control-plane employs a centralized scheduler to compute the channel allocations and a signaling daemon to generate configuration signals to switches. In a nutshell, USN demonstrated the ability to build and operate a stable national-scale switched network. (b) Structured Network Research Experiments: A number of network research experiments have been conducted on USN that cannot be easily supported over existing network facilities, including test-beds and production networks. It settled an open matter by demonstrating
Zhang, Rui; Mao, Shao-Jie; Zhang, Hong-Jun; Zhang, You-Liang; Zhu, Yu
When high level architecture is used to build complex systems in support of modeling and simulation, the problems are low level of interoperability and poor reusage. Based on the concept of service-oriented and distributed technologies, a service bus of network-centric simulation is proposed. Definite the concept of community of service and service bus, establish the architecture of simulation service bus and its implementation framework, analyze three key technologies of its implementation process. The primary research and practice show that: the proposed simulation service bus can support to run community simulation tasks based on Internet and provide a reference for building a service-oriented environment of network centric simulation.
Khurshid, Anjum; Nauman, Elizabeth; Carton, Tom; Horswell, Ron
The state of Louisiana, like the nation as a whole, is facing the salient challenge of improving population health and efficiency of healthcare delivery. Research to inform innovations in healthcare will best enhance this effort if it is timely, efficient, and patient-centered. The Louisiana Clinical Data Research Network (LACDRN) will increase the capacity to conduct robust comparative effectiveness research by building a health information technology infrastructure that provides access to comprehensive clinical data for more than 1 million patients statewide. To ensure that network-based research best serves its end-users, the project will actively engage patients and providers as key informants and decision-makers in the implementation of LACDRN. The network's patient-centered research agenda will prioritize patients’ and clinicians’ needs and aim to support evidence-based decisions on the healthcare they receive and provide, to optimize patient outcomes and quality of life. PMID:24821735
Vogt, Thomas M; Elston-Lafata, Jennifer; Tolsma, Dennis; Greene, Sarah M
Science is the basis of medicine. Good science leads to better decisions and more effective systems to support those decisions. Most individuals associate science primarily with academic institutions. However, top-quality research relevant to managing the health of populations and the care of specific clinical conditions is increasingly being carried out by investigators working in integrated healthcare systems. This introduction outlines the activities of the HMO Research Network, whose researchers have made and continue to make important contributions to the field of health research. Its objective is to inform readers of the activities and value of systems-based health research. We describe the importance and extent of the research conducted by HMO Research Network members, as well as the advantages of conducting research in such settings.
van Eck, T.; Giardini, D.; Bossu, R.; Wiemer, S.
NERIES (Network of Research Infrastructures for European Seismology) is an Integrated Infrastructure Initiative (I3) project within the Sixth Framework Programme of the European Commission (EC). The project consortium consists of 25 participants from 13 different European countries. It is currently the largest earth science project ever funded by the EC. The goal of NERIES is to integrate European seismological observatories and research institutes into one integrated cyber-infrastructure for seismological data serving the research community, civil protection authorities and the general public. The EC provides funds for the networking and research. The participants provide the necessary hardware investments, mostly through national resources. NERIES consists of 13 subprojects (networking and research activities) and 5 facilities providing access through grants (Transnational Access). The project is coordinated by ORFEUS in close cooperation with the EMSC. The individual subprojects address different issues such as: extension of the Virtual European Broadband Seismic Network (VEBSN) from 140 to about 500 stations, implementing the core European Integrated Waveform Data Archive (EIDA) consisting of ODC-KNMI, GFZ, INGV and IPGP and a distributed archive of historical Data. Providing access to data gathered by acceleration networks within Europe and its surroundings and deploys Ocean Bottom Seismometers in coordination with relevant Ocean bottom projects like ESONET. Tot facilitate access to this diverse and distributed data NERIES invests a significant portion of its resources to implementing a portal for which a beta release is planned to be release in the autumn of 2008. The research project main goal is to produce products and tools facilitating data interpretation and analysis. These tools include a European reference (velocity) model, real-time hazard tools, shakemaps and lossmaps, site response determination software and tools, and automatic tools to manage and
Yan, Li-Xing; Xu, Yan; Meng, Zhong-Hua; Kong, Chang-Hong; Wang, Jian-Min; Jin, Zhen-Liang; Wu, Shi-Ding; Chen, Chang-Shui; Luo, Ling-Fei
This research was aimed to develop the first level blood information centralized database and real time communication network at a province area in China. Multiple technology like local area network database separate operation, real time data concentration and distribution mechanism, allopatric backup, and optical fiber virtual private network (VPN) were used. As a result, the blood information centralized database and management system were successfully constructed, which covers all the Zhejiang province, and the real time exchange of blood data was realised. In conclusion, its implementation promote volunteer blood donation and ensure the blood safety in Zhejiang, especially strengthen the quick response to public health emergency. This project lays the first stone of centralized test and allotment among blood banks in Zhejiang, and can serve as a reference of contemporary blood bank information systems in China.
Cagnazzo, Luca; Taticchi, Paolo; Bidini, Gianni; Baglieri, Enzo
New business models and theories are developing nowadays towards collaborative environments direction, and many new tools in sustaining companies involved in these organizations are emerging. Among them, a plethora of methodologies to analyze their needs are already developed for single companies. Few academic works are available about Enterprise Networks (ENs) need analysis. This paper presents the learning from an action research (AR) in the mechatronics sector: AR has been used in order to experience the issue of evaluating network needs and therefore define, develop, and test a complete framework for network evaluation. Reflection on the story in the light of the experience and the theory is presented, as well as extrapolation to a broader context and articulation of usable knowledge.
Kitts, Christopher A.
The development and implementation of the Automated Space System Experimental Testbed (ASSET) space operations and control network, is reported on. This network will serve as a command and control architecture for spacecraft operations and will offer a real testbed for the application and validation of advanced autonomous spacecraft operations strategies. The proposed network will initially consist of globally distributed amateur radio ground stations at locations throughout North America and Europe. These stations will be linked via Internet to various control centers. The Stanford (CA) control center will be capable of human and computer based decision making for the coordination of user experiments, resource scheduling and fault management. The project's system architecture is described together with its proposed use as a command and control system, its value as a testbed for spacecraft autonomy research, and its current implementation.
Kitts, Christopher A.
The development and implementation of the Automated Space System Experimental Testbed (ASSET) space operations and control network, is reported on. This network will serve as a command and control architecture for spacecraft operations and will offer a real testbed for the application and validation of advanced autonomous spacecraft operations strategies. The proposed network will initially consist of globally distributed amateur radio ground stations at locations throughout North America and Europe. These stations will be linked via Internet to various control centers. The Stanford (CA) control center will be capable of human and computer based decision making for the coordination of user experiments, resource scheduling and fault management. The project's system architecture is described together with its proposed use as a command and control system, its value as a testbed for spacecraft autonomy research, and its current implementation.
Graham, Amanda L; Byron, M. Justin; Niaura, Raymond S; Abrams, David B
Background Smoking remains one of the most pressing public health problems in the United States and internationally. The concurrent evolution of the Internet, social network science, and online communities offers a potential target for high-yield interventions capable of shifting population-level smoking rates and substantially improving public health. Objective Our objective was to convene leading practitioners in relevant disciplines to develop the core of a strategic research agenda on online social networks and their use for smoking cessation, with implications for other health behaviors. Methods We conducted a 100-person, 2-day, multidisciplinary workshop in Washington, DC, USA. Participants worked in small groups to formulate research questions that could move the field forward. Discussions and resulting questions were synthesized by the workshop planning committee. Results We considered 34 questions in four categories (advancing theory, understanding fundamental mechanisms, intervention approaches, and evaluation) to be the most pressing. Conclusions Online social networks might facilitate smoking cessation in several ways. Identifying new theories, translating these into functional interventions, and evaluating the results will require a concerted transdisciplinary effort. This report presents a series of research questions to assist researchers, developers, and funders in the process of efficiently moving this field forward. PMID:22182518
Cobb, Nathan K; Graham, Amanda L; Byron, M Justin; Niaura, Raymond S; Abrams, David B
Smoking remains one of the most pressing public health problems in the United States and internationally. The concurrent evolution of the Internet, social network science, and online communities offers a potential target for high-yield interventions capable of shifting population-level smoking rates and substantially improving public health. Our objective was to convene leading practitioners in relevant disciplines to develop the core of a strategic research agenda on online social networks and their use for smoking cessation, with implications for other health behaviors. We conducted a 100-person, 2-day, multidisciplinary workshop in Washington, DC, USA. Participants worked in small groups to formulate research questions that could move the field forward. Discussions and resulting questions were synthesized by the workshop planning committee. We considered 34 questions in four categories (advancing theory, understanding fundamental mechanisms, intervention approaches, and evaluation) to be the most pressing. Online social networks might facilitate smoking cessation in several ways. Identifying new theories, translating these into functional interventions, and evaluating the results will require a concerted transdisciplinary effort. This report presents a series of research questions to assist researchers, developers, and funders in the process of efficiently moving this field forward.
Curtis McMillen, J; Lenze, Shannon L; Hawley, Kristin M; Osborne, Victoria A
Practice-based research networks (PBRNs)-collaborations of practice settings that work together to generate research knowledge-are underused in mental health services research. This article proposes an agenda for mental health services research that uses a variety of PBRN structures and that focuses on what really happens in practice, the effectiveness of practice innovations in real world care, the challenges of implementing evidence supported interventions, modification of clinician behavior, and assessment of the effect of mental health policy changes on practice. The challenges of conducting research within PBRNs are substantial, including difficulties in maintaining positive member relations, securing ongoing funding, sustaining productivity, overcoming IRB entanglements and achieving both scientific excellence in recruitment and measurement validity and utility for practitioner members. However, the awareness of these challenges allows researchers and practitioners to build networks that creatively overcome them and that infuse mental health services research with heavy doses of the realities of everyday clinical practice.
Arain, Mubashir; Pyne, Sarah; Thornton, Nigel; Palmer, Susan; Sharma, Ricky A
The involvement of consumers and the general public in improving cancer services is an important component of health services. However, consumer involvement in cancer research is relatively unexplored. The objective of this study was to explore different ways of involving consumers in cancer research in one regional network. Thames Valley Cancer Network Consumer Research Partnership (CRP) group was formed in 2009. The group consists of consumers and professionals to help in promoting consumer involvement in Cancer Research in the Thames Valley. This study evaluated the project of consumer involvement in cancer research in the Thames Valley from March 2010 to March 2011. We used different indices to judge the level of consumer involvement: number of projects involving consumers through the group, types of projects, level of involvement (ranged from consultation on research documents to collaborating in preparing grant applications) and the methods of involving consumers in cancer research. Fifteen projects were submitted to the CRP group during the 12-month period studied. Of these, eight projects were clinical trials, three were qualitative research projects, two were patients' surveys and two were non-randomized interventional studies. Seven projects requested consumer involvement on patient information sheets for clinical trials. Of these seven applications, three also requested consumers' help in designing research questionnaires and another three requested that consumers should be involved in their project management group. In addition, four projects involved consumers in the proposal development phase and another four projects asked for advice on how to increase trial recruitment, conduct patient interviews or help with grant applications. The creation of the CRP and this audit of its activity have documented consumer involvement in cancer research in the Thames Valley. We have clearly shown that consumers can be involved in designing and managing cancer
McClure, Charles R.; And Others
This book provides an overview and status report on the progress made in developing the National Research and Education Network (NREN) as of early 1991. It reports on a number of investigations that provide a research and policy perspective on the NREN and computer-mediated communication (CMC), and brings together key source documents that have…
This article provides an analysis of the Collaborative Action Research Network's (CARN) origins and development since its foundation in 1976. The author brings the unique perspective of active involvement in CARN almost from its inception, and editorship for many years of its journal "Educational Action Research". Cultural-historical…
Pettit, Michael; Serykh, Darya; Green, Christopher D
In our current moment, there is considerable interest in networks, in how people and things are connected. This essay outlines one approach that brings together insights from actor-network theory, social network analysis, and digital history to interpret past scientific activity. Multispecies network analysis (MNA) is a means of understanding the historical interactions among scientists, institutions, and preferred experimental animals. A reexamination of studies of sexual behavior funded by the Committee for Research in Problems of Sex between the 1920s and the 1940s demonstrates the applicability of MNA to clarifying the relations that sustained this area of psychology. The measures of weighted degree and betweenness can highlight which nodes (whether organisms or institutions) were particularly "central" to this network. Rats featured as the animals most widely studied during this period, but the analysis also reveals distinct institutional and disciplinary cultures where different species were favored as either surrogates for humans or representatives of more general biological groups.
Schosser, Alexandra; Kasper, Siegfried
Although effective treatment for mood and anxiety disorders have been available for more than 40 years, 30-50% of depressed patients and 25% of patients with anxiety disorder do not respond sufficiently to first-line treatment with antidepressants. Genetic factors are supposed to play a major role in both variation of treatment response and incidence of adverse effects to medication. So far, candidate genes of pharmacokinetic and pharmacodynamic pathways of antidepressants have been investigated, and associations between several candidate genes and response to antidepressants are reported. Two functional polymorphisms of the serotonin transporter gene, 5-HTTLPR and STin2 have been investigated in a large number of pharmacogenetic studies of depression; other candidate genes include serotonin receptor genes, brain-derived neurotrophic factor, P-glycoprotein (located in the blood-brain barrier), G-proteins, TPH1 and TPH2, MAOA, the noradrenaline transporter gene, FKBP5, or cytochrome P450 (CYP450) genes. CYP450 genes play a major role in the metabolism of a substantial part of psychotropics, including antidepressants, and the first estimates of dosage adjustments for antidepressants have been provided based on metabolizer status. Genome-wide association studies that use large numbers of single-nucleotide polymorphisms to screen the entire genome for alleles that influence a trait are now feasible, and the results of the first genome-wide association studies of antidepressant treatment outcome will soon be available. The current review not only updates pharmacogenetic research in depression but also focuses on antidepressant treatment response in anxiety disorders.
Hoffman, James M.; Haidar, Cyrine E.; Wilkinson, Mark R.; Crews, Kristine R.; Baker, Donald K.; Kornegay, Nancy M.; Yang, Wenjian; Pui, Ching-Hon; Reiss, Ulrike M.; Gaur, Aditya H.; Howard, Scott C.; Evans, William E.; Broeckel, Ulrich; Relling, Mary V.
Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children’s Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1559 patients have been enrolled, and 4 gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. PMID:24619595
Campbell, Jared M; Bateman, Emma; Stephenson, Matthew D; Bowen, Joanne M; Keefe, Dorothy M; Peters, Micah D J
Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.
Hoffman, James M; Haidar, Cyrine E; Wilkinson, Mark R; Crews, Kristine R; Baker, Donald K; Kornegay, Nancy M; Yang, Wenjian; Pui, Ching-Hon; Reiss, Ulrike M; Gaur, Aditya H; Howard, Scott C; Evans, William E; Broeckel, Ulrich; Relling, Mary V
Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. © 2014 Wiley Periodicals, Inc.
Daly, Jeanette M; Bay, Camden; Levy, Barcey T
Although the fecal immunochemical test (FIT) has recently emerged as an effective and affordable colorectal cancer screening option, many family physician offices continue to use guaiac-based tests. The purpose of this study was to assess the use of FITs in the Iowa Research Network and to assess physicians' knowledge about FITs. A cover letter and questionnaire were faxed twice to the 291 physician members followed up by a mailing. One hundred and seven (37%) questionnaires were returned. Participants' mean age was 55 years with 78 male responders. Fifty-two (49%) of the physician's offices were in a nonmetro area. Fifty-one (49%) reported using guaiac-based tests and 39 (39%) reported using FITs. Many physicians were unsure of the answers for the FIT knowledge questions. FIT use is not widespread in Iowa Research Network physician offices, and not all physicians are aware of the type of fecal occult blood test being conducted in their office.
Corvol, Harriet; De Giacomo, Anthony; Eng, Celeste; Seibold, Max; Ziv, Elad; Chapela, Rocio; Rodriguez-Santana, Jose R.; Rodriguez-Cintron, William; Thyne, Shannon; Watson, H. Geoffrey; Meade, Kelley; LeNoir, Michael; Avila, Pedro C.; Choudhry, Shweta; Burchard, Esteban Gonz!lez
Objective A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients. Methods Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene–gene interactions were tested by using multiple linear regression analyses. Results No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene–gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol. Conclusion Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry. PMID:19503017
Aroke, Edwin N; Crawford, Sybil L; Dungan, Jennifer R
Up to 55% of patients who are administered ketamine experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury; however, to date, no studies have investigated genetic association of ketamine-induced EP in healthy patients. The aim of the study was to investigate the feasibility and sample sizes required to explore the relationship between CYP2B6*6 and GRIN2B single-nucleotide polymorphisms and ketamine-induced EP. This cross-sectional, pharmacogenetic candidate, gene pilot study recruited 75 patients having minor elective outpatient surgeries. EP was measured with the Clinician Administered Dissociative State Scale. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 and rs1806191) single-nucleotide polymorphisms and ketamine-induced EP occurrence and severity were tested using logistic and linear regression. Forty-seven patients (63%) received ketamine and were genotyped, and 40% of them experienced EP. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p > .10). Exploratory analysis of nongenotype models containing age, ketamine dose, duration of anesthesia, and time from ketamine administration to assessment for EP significantly predicted EP occurrence (p = .001) and severity (p = .007). This pilot study demonstrates feasibility for implementing a pharmacogenetic study in a clinical setting, and we estimate that between 380 and 570 cases will be needed to adequately power future genetic association studies. Younger age, higher dose, and longer duration of anesthesia significantly predicted EP occurrence and severity among our pilot sample. Although the small sample size limited our ability to demonstrate significant genotype differences, we generated effect sizes, sample size estimates, and nongenetic covariates information in order to support future pharmacogenetic study design for evaluating this adverse event.
Gammal, Roseann S; Crews, Kristine R; Haidar, Cyrine E; Hoffman, James M; Baker, Donald K; Barker, Patricia J; Estepp, Jeremie H; Pei, Deqing; Broeckel, Ulrich; Wang, Winfred; Weiss, Mitchell J; Relling, Mary V; Hankins, Jane
After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. Copyright © 2016 by the American Academy of Pediatrics.
Corvol, Harriet; De Giacomo, Anthony; Eng, Celeste; Seibold, Max; Ziv, Elad; Chapela, Rocio; Rodriguez-Santana, Jose R; Rodriguez-Cintron, William; Thyne, Shannon; Watson, H Geoffrey; Meade, Kelley; LeNoir, Michael; Avila, Pedro C; Choudhry, Shweta; Burchard, Esteban González
A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients. Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses. No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol. Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.
Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C
(1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.
Gammal, Roseann S.; Haidar, Cyrine E.; Hoffman, James M.; Baker, Donald K.; Barker, Patricia J.; Estepp, Jeremie H.; Pei, Deqing; Broeckel, Ulrich; Wang, Winfred; Weiss, Mitchell J.; Relling, Mary V.; Hankins, Jane
After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. PMID:27335380
Petain, Aurélie; Kattygnarath, Darouna; Azard, Julie; Chatelut, Etienne; Delbaldo, Catherine; Geoerger, Birgit; Barrois, Michel; Séronie-Vivien, Sophie; LeCesne, Axel; Vassal, Gilles
The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m(2) and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma alpha1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients). Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P<0.05). By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.
Ribisl, Kurt M; Fernandez, Maria E; Friedman, Daniela B; Hannon, Peggy A; Leeman, Jennifer; Moore, Alexis; Olson, Lindsay; Ory, Marcia; Risendal, Betsy; Sheble, Laura; Taylor, Vicky M; Williams, Rebecca S; Weiner, Bryan J
The Cancer Prevention and Control Research Network (CPCRN) is a thematic network dedicated to accelerating the adoption of evidence-based cancer prevention and control practices in communities by advancing dissemination and implementation science. Funded by the Centers for Disease Control and Prevention and National Cancer Institute, CPCRN has operated at two levels: Each participating network center conducts research projects with primarily local partners as well as multicenter collaborative research projects with state and national partners. Through multicenter collaboration, thematic networks leverage the expertise, resources, and partnerships of participating centers to conduct research projects collectively that might not be feasible individually. Although multicenter collaboration is often advocated, it is challenging to promote and assess. Using bibliometric network analysis and other graphical methods, this paper describes CPCRN's multicenter publication progression from 2004 to 2014. Searching PubMed, Scopus, and Web of Science in 2014 identified 249 peer-reviewed CPCRN publications involving two or more centers out of 6,534 total. The research and public health impact of these multicenter collaborative projects initiated by CPCRN during that 10-year period were then examined. CPCRN established numerous workgroups around topics such as: 2-1-1, training and technical assistance, colorectal cancer control, federally qualified health centers, cancer survivorship, and human papillomavirus. This paper discusses the challenges that arise in promoting multicenter collaboration and the strategies that CPCRN uses to address those challenges. The lessons learned should broadly interest those seeking to promote multisite collaboration to address public health problems, such as cancer prevention and control.
Protecting participants in family medicine research: a consensus statement on improving research integrity and participants' safety in educational research, community-based participatory research, and practice network research.
Hueston, William J; Mainous, Arch G; Weiss, Barry D; Macaulay, Ann C; Hickner, John; Sherwood, Roger A
Recent events that include the deaths of research subjects and the falsification of data have drawn greater scrutiny on assuring research data integrity and protecting participants. Several organizations have created guidelines to help guide researchers working in the area of clinical trials and ensure that their research is safe and valid. However, family medicine researchers often engage in research that differs from a typical clinical trial. Investigators working in the areas of educational research, community-based participatory research, and practice-based network research would benefit from similar recommendations to guide their own research. With funding from the US Office of Research Integrity and the Association of American Medical Colleges, we convened a panel to review issues of data integrity and participant protection in educational research, community-based participatory research, and research conducted by practice-based networks. The panel generated 11 recommendations for researchers working in these areas. Three key recommendations include the need for (1) all educational research to undergo review and approval by an institutional review board (IRB), (2) community-based participatory research to be approved not just by an IRB but also by appropriate community representatives, and (3) practice-based researchers to undertake only valid and meaningful studies that can be reviewed by a central IRB, rather than separate IRBs for each participating practice.
Xu, Hang; Su, Shi; Tang, Wuji; Wei, Meng; Wang, Tao; Wang, Dongjin; Ge, Weihong
A large number of warfarin pharmacogenetics algorithms have been published. Our research was aimed to evaluate the performance of the selected pharmacogenetic algorithms in patients with surgery of heart valve replacement and heart valvuloplasty during the phase of initial and stable anticoagulation treatment. 10 pharmacogenetic algorithms were selected by searching PubMed. We compared the performance of the selected algorithms in a cohort of 193 patients during the phase of initial and stable anticoagulation therapy. Predicted dose was compared to therapeutic dose by using a predicted dose percentage that falls within 20% threshold of the actual dose (percentage within 20%) and mean absolute error (MAE). The average warfarin dose for patients was 3.05±1.23mg/day for initial treatment and 3.45±1.18mg/day for stable treatment. The percentages of the predicted dose within 20% of the therapeutic dose were 44.0±8.8% and 44.6±9.7% for the initial and stable phases, respectively. The MAEs of the selected algorithms were 0.85±0.18mg/day and 0.93±0.19mg/day, respectively. All algorithms had better performance in the ideal group than in the low dose and high dose groups. The only exception is the Wadelius et al. algorithm, which had better performance in the high dose group. The algorithms had similar performance except for the Wadelius et al. and Miao et al. algorithms, which had poor accuracy in our study cohort. The Gage et al. algorithm had better performance in both phases of initial and stable treatment. Algorithms had relatively higher accuracy in the >50years group of patients on the stable phase.
Ovejero-Benito, María C; Muñoz-Aceituno, Ester; Reolid, Alejandra; Saiz-Rodríguez, Miriam; Abad-Santos, Francisco; Daudén, Esteban
Pharmacogenetics is the study of variations in DNA sequence related to drug response. Moreover, the evolution of biotechnology and the sequencing of human DNA have allowed the creation of pharmacogenomics, a branch of genetics that analyzes human genes, the RNAs and proteins encoded by them, and the inter-and intra-individual variations in expression and function in relation to drug response. Pharmacogenetics and pharmacogenomics are being used to search for biomarkers that can predict response to systemic treatments, including those for moderate-to-severe psoriasis. Psoriasis is a chronic inflammatory disease with an autoimmune contribution. Although its etiology remains unknown, genetic, epigenetic, and environmental factors play a role in its development. Diverse systemic and biologic therapies are used to treat moderate-to-severe psoriasis. However, these treatments are not curative, and patients exhibit a wide range of responses to them. Moderate-to-severe psoriasis is usually treated with systemic immunomodulators such as acitretin, ciclosporin, and methotrexate. Anti-tumor necrosis factor (TNF) drugs (adalimumab, etanercept, or infliximab) are the first-line treatment for patients resistant to conventional systemic therapies. Although these therapies are very efficient, around 30-50% of patients have inadequate response. Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 and is used for moderate-to-severe psoriasis. New drugs (apremilast, brodalumab, guselkumab, ixekizumab, and secukinumab) have recently been approved for psoriasis. However, response rates to systemic treatments for moderate-to-severe psoriasis range from 35 to 80%, so it is necessary to identify non-invasive biomarkers that could help predict treatment outcomes of these therapies and individualize care for patients with psoriasis. These biomarkers could improve patient quality of life and reduce health costs and potential side effects. Pharmacogenetic studies
Turner, S T; Schwartz, G L; Chapman, A B; Hall, W D; Boerwinkle, E
Pharmacogenetic investigation seeks to identify genetic factors that contribute to interpatient and interdrug variation in responses to antihypertensive drug therapy. Classical studies have characterized single gene polymorphisms of drug metabolizing enzymes that are responsible for large interindividual differences in pharmacokinetic responses to several antihypertensive drugs. Progress is being made using candidate gene and genome scanning approaches to identify and characterize many additional genes influencing pharmacodynamic mechanisms that contribute to interindividual differences in responses to antihypertensive drug therapy. Knowledge of polymorphic variation in these genes will help to predict individual patients' blood pressure responses to antihypertensive drug therapy and may also provide new insights into molecular mechanisms responsible for elevation of blood pressure.
Rosenbloom, S Trent; Harris, Paul; Pulley, Jill; Basford, Melissa; Grant, Jason; DuBuisson, Allison; Rothman, Russell L
The Mid-South Clinical Data Research Network (CDRN) encompasses three large health systems: (1) Vanderbilt Health System (VU) with electronic medical records for over 2 million patients, (2) the Vanderbilt Healthcare Affiliated Network (VHAN) which currently includes over 40 hospitals, hundreds of ambulatory practices, and over 3 million patients in the Mid-South, and (3) Greenway Medical Technologies, with access to 24 million patients nationally. Initial goals of the Mid-South CDRN include: (1) expansion of our VU data network to include the VHAN and Greenway systems, (2) developing data integration/interoperability across the three systems, (3) improving our current tools for extracting clinical data, (4) optimization of tools for collection of patient-reported data, and (5) expansion of clinical decision support. By 18 months, we anticipate our CDRN will robustly support projects in comparative effectiveness research, pragmatic clinical trials, and other key research areas and have the capacity to share data and health information technology tools nationally. PMID:24821742
This dissertation is a study of scientific collaboration at the Center for Embedded Networked Sensing (CENS), a modern, multi-disciplinary, distributed laboratory involved in sensor network research. By use of survey research and network analysis, this dissertation examines the collaborative ecology of CENS in terms of three networks of…
This dissertation is a study of scientific collaboration at the Center for Embedded Networked Sensing (CENS), a modern, multi-disciplinary, distributed laboratory involved in sensor network research. By use of survey research and network analysis, this dissertation examines the collaborative ecology of CENS in terms of three networks of…
You, Han; Ni, Jingyun; Barber, Michael; Scherngell, Thomas; Hu, Yuanjia
Better understanding of China's landscape in oncology drug research is of great significance for discovering anti-cancer drugs in future. This article differs from previous studies by focusing on Chinese oncology drug research communities in co-publication networks at the institutional level. Moreover, this research aims to explore structures and behaviors of relevant research units by thematic community analysis and to address policy recommendations. This research used social network analysis to define an institutions network and to identify a community network which is characterized by thematic content. A total of 675 sample articles from 2008 through 2012 were retrieved from the Science Citation Index Expanded (SCIE) database of Web of Science, and top institutions and institutional pairs are highlighted for further discussion. Meanwhile, this study revealed that institutions based in the Chinese mainland are located in a relatively central position, Taiwan's institutions are closely assembled on the side, and Hong Kong's units located in the middle of the Chinese mainland's and Taiwan's. Spatial division and institutional hierarchy are still critical barriers to research collaboration in the field of anti-cancer drugs in China. In addition, the communities focusing on hot research areas show the higher nodal degree, whereas communities giving more attention to rare research subjects are relatively marginalized to the periphery of network. This paper offers policy recommendations to accelerate cross-regional cooperation, such as through developing information technology and increasing investment. The brokers should focus more on outreach to other institutions. Finally, participation in topics of common interest is conducive to improved efficiency in research and development (R&D) resource allocation.
You, Han; Ni, Jingyun; Barber, Michael; Scherngell, Thomas
Objective Better understanding of China’s landscape in oncology drug research is of great significance for discovering anti-cancer drugs in future. This article differs from previous studies by focusing on Chinese oncology drug research communities in co-publication networks at the institutional level. Moreover, this research aims to explore structures and behaviors of relevant research units by thematic community analysis and to address policy recommendations. Methods This research used social network analysis to define an institutions network and to identify a community network which is characterized by thematic content. Results A total of 675 sample articles from 2008 through 2012 were retrieved from the Science Citation Index Expanded (SCIE) database of Web of Science, and top institutions and institutional pairs are highlighted for further discussion. Meanwhile, this study revealed that institutions based in the Chinese mainland are located in a relatively central position, Taiwan’s institutions are closely assembled on the side, and Hong Kong’s units located in the middle of the Chinese mainland’s and Taiwan’s. Spatial division and institutional hierarchy are still critical barriers to research collaboration in the field of anti-cancer drugs in China. In addition, the communities focusing on hot research areas show the higher nodal degree, whereas communities giving more attention to rare research subjects are relatively marginalized to the periphery of network. Conclusions This paper offers policy recommendations to accelerate cross-regional cooperation, such as through developing information technology and increasing investment. The brokers should focus more on outreach to other institutions. Finally, participation in topics of common interest is conducive to improved efficiency in research and development (R&D) resource allocation. PMID:25937775
Parke, Courtney; Cook, Julia; Carton, Thomas; Rao, Sohail
Background Mapping of the human genome and technological advancements allowing storage and rapid retrieval of healthcare data have heralded a new phase in clinical medicine and have served as a catalyst for the advent of personalized medicine. The use of health information databases provides a unique opportunity to investigate questions of great complexity and real-world application in a way that is most useful in providing high quality, safe, and cost-effective clinical care to patients. Methods The Louisiana Clinical Data Research Network (LACDRN) aims to streamline the workflow of multiinstitutional clinical studies and to dramatically expand the clinical research resources available to local investigators. The LACDRN contains health information for more than 1 million patients in Southeast Louisiana and is a rich resource for researchers to conduct retrospective or observational trials and to recruit patients for prospective studies. Results The LACDRN is part of a large-scale initiative by the Patient-Centered Outcomes Research Institute to create a national electronic health record network that enables the timely initiation and completion of comparative effectiveness research in a coordinated effort. For the first time, network research will be guided in part by input from patients and caregivers, increasing their engagement in the research process. Conclusion The establishment of the LACDRN is a unique opportunity for clinicians to take part in an innovative national initiative designed to offer new clinical research options for patients and to carry out cutting-edge translational, clinical, and health services research. PMID:25598739
Jimenez-Castellanos, Ana; Ramirez-Robles, Maximo; Shousha, Amany; Bagayoko, Cheick Oumar; Perrin, Caroline; Zolfo, Maria; Cuzin, Asa; Roland, Alima; Aryeetey, Richmond; Maojo, Victor
Traditionally, participation of African researchers in top Biomedical Informatics (BMI) scientific journals and conferences has been scarce. Looking beyond these numbers, an educational goal should be to improve overall research and, therefore, to increase the number of scientists/authors able to produce and publish high quality research. In such scenario, we are carrying out various efforts to expand the capacities of various institutions located at four African countries - Egypt, Ghana, Cameroon and Mali - in the framework of a European Commission-funded project, AFRICA BUILD. This project is currently carrying out activities such as e-learning, collaborative development of informatics tools, mobility of researchers, various pilot projects, and others. Our main objective is to create a self-sustained South-South network of BMI developers.
Conklin, James; Lusk, Elizabeth; Harris, Megan; Stolee, Paul
The purpose of this paper is to describe and reflect on the role of knowledge brokers (KBs) in the Seniors Health Research Transfer Network (SHRTN). The paper reviews the relevant literature on knowledge brokering, and then describes the evolving role of knowledge brokering in this knowledge network. The description of knowledge brokering provided here is based on a developmental evaluation program and on the experiences of the authors. Data were gathered through qualitative and quantitative methods, analyzed by the evaluators, and interpreted by network members who participated in sensemaking forums. The results were fed back to the network each year in the form of formal written reports that were widely distributed to network members, as well as through presentations to the network's members. The SHRTN evaluation and our experiences as evaluators and KBs suggest that a SHRTN KB facilitates processes of learning whereby people are connected with tacit or explicit knowledge sources that will help them to resolve work-related challenges. To make this happen, KBs engage in a set of relational, technical, and analytical activities that help communities of practice (CoPs) to develop and operate, facilitate exchanges among people with similar concerns and interests, and help groups and individuals to create, explore, and apply knowledge in their practice. We also suggest that the role is difficult to define, emergent, abstract, episodic, and not fully understood. The KB role within this knowledge network has developed and matured over time. The KB adapts to the social and technical affordances of each situation, and fashions a unique and relevant process to create relationships and promote learning and change. The ability to work with teams and to develop relevant models and feasible approaches are critical KB skills. The KB is a leader who wields influence rather than power, and who is prepared to adopt whatever roles and approaches are needed to bring about a valuable